Tumor-Specific Catalysis-Mediated Enhanced Chemodynamic Therapy in Synergy with Mitophagy Inhibition Improves Therapeutic Efficacy in Endometrial Cancer

BackgroundChemodynamic therapy (CDT) relies on tumor microenvironment (e.g. high H2O2 level) responsive Fenton-like reactions to produce hydroxyl radicals (·OH) against tumors. However, endogenous H2O2 is insufficient for effective chemodynamic reactions.ResultsAn NAD(P)H: quinone oxidoreductase 1 (NQO1)highCatalase (CAT)low therapeutic window for the use of NQO1 bioactive drug β-lapachone (β-Lap) was firstly identified in endometrial cancer (EC). Accompanied by NADH depletion, β-Lap was catalyzed by NQO1 to produce excess H2O2 initiating oxidative stress, which selectively suppressed NQO1high EC cell proliferation, induced DNA double-strand breaks and promoted apoptosis. SiRNA-mediated NQO1 knockdown or dicoumarol rescued NQO1high EC cells from β-Lap-induced cytotoxicity. Arginine-glycine-aspartic acid (RGD)-functionalized iron-based metal organic frameworks-MOF(Fe) further promoted the conversion of accumulated H2O2 into highly oxidative ·OH, and in turn exacerbated the oxidative damage to RGD-positive target cells. Mitophagy inhibition by Mdivi-1 blocked a powerful antioxidant defense approach, ultimately ensuring the antitumor efficacy of stepwise amplified ROS signals. The tumor growth inhibition rate was about 85.92%.ConclusionsTumor specific chemotherapy in combination with CDT-triggered therapeutic modality presented unprecedented therapeutic advantages for the treatment of NQO1+ advanced type I or type II EC.

Novel CD37, Humanized CD37 and Bi-Specific Humanized CD37-CD19 CAR-T Cells Specifically Target Lymphoma

CD19 and CD37 proteins are highly expressed in B-cell lymphoma and have been successfully targeted with different monotherapies, including chimeric antigen receptor (CAR)-T cell therapy. The goal of this study was to target lymphoma with novel CD37, humanized CD37, and bi-specific humanized CD37-CD19 CAR-T cells. A novel mouse monoclonal anti-human CD37 antibody (clone 2B8D12F2D4) was generated with high binding affinity for CD37 antigen (KD = 1.6 nM). The CD37 antibody specifically recognized cell surface CD37 protein in lymphoma cells and not in multiple myeloma or other types of cancer. The mouse and humanized CD37-CAR-T cells specifically killed Raji and CHO-CD37 cells and secreted IFN-gamma. In addition, we generated bi-specific humanized hCD37-CD19 CAR-T cells that specifically killed Raji cells, CHO-CD37, and Hela-CD19 cells and did not kill control CHO or Hela cells. Moreover, the hCD37-CD19 CAR-T cells secreted IFN-gamma against CD37-positive and CD19-positive target CHO-CD37, Hela-CD19 cells, respectively, but not against CD19 and CD37-negative parental cell line. The bi-specific hCD37-CD19 significantly inhibited Raji xenograft tumor growth and prolonged mouse survival in NOD scid gamma mouse (NSG) mouse model. This study demonstrates that novel humanized CD37 and humanized CD37-CD19 CAR-T cells specifically targeted either CD37 positive or CD37 and CD19-positive cells and provides a basis for future clinical studies.

Smaller Volume in Left-Lateralized Brain Structures Correlates with Greater Experience of Negative Non-target Emotions in Neurodegenerative Diseases

Subjective emotional experience that is congruent with a given situation (i.e., target emotions) is critical for human survival (e.g., feeling disgusted in response to contaminated food motivates withdrawal behaviors). Neurodegenerative diseases including frontotemporal dementia and Alzheimer’s disease affect brain regions critical for cognitive and emotional functioning, resulting in increased experience of emotions incongruent with the situation (i.e., non-target emotions, such as feeling happy when seeing someone grieving). We examined neuroanatomical correlates of subjective experience of non-target emotions in 147 patients with neurodegenerative diseases and 26 healthy individuals. Participants watched three films intended to elicit particular target emotions and rated their experience of negative and positive target and non-target emotions after watching each film. We found that smaller volume in left hemisphere regions (e.g., caudate, putamen, and dorsal anterior insula) was associated with greater experience of negative non-target emotions. Follow-up analyses confirmed that these effects were left-lateralized. No correlates emerged for positive non-target emotions. These findings suggest that volume loss in left-hemisphere regions produces a more diffuse, incongruent experience of non-target emotions. These findings provide a potential neuroanatomical basis for understanding how subjective emotional experience is constructed in the brain and how this can be disrupted in neurodegenerative disease.

T Cells Expressing a TCR-Like Antibody Selected Against the Heteroclitic Variant of a Shared MAGE-A Epitope Do Not Recognise the Cognate Epitope

Antibodies-recognising peptides bound to the major histocompatibility complex (pMHC) represent potentially valuable and promising targets for chimeric antigen receptor (CAR) T cells to treat patients with cancer. Here, a human phage-Fab library has been selected using HLA-A2 complexed with a heteroclitic peptide variant from an epitope shared among multiple melanoma-associated antigens (MAGEs). DNA restriction analyses and phage ELISAs confirmed selection of unique antibody clones that specifically bind to HLA-A2 complexes or HLA-A2-positive target cells loaded with native or heteroclitic peptide. Antibodies selected against heteroclitic peptide, in contrast to native peptide, demonstrated significantly lower to even negligible binding towards native peptide or tumour cells that naturally expressed peptides. The binding to native peptide was not rescued by phage panning with antigen-positive tumour cells. Importantly, when antibodies directed against heteroclitic peptides were engineered into CARs and expressed by T cells, binding to native peptides and tumour cells was minimal to absent. In short, TCR-like antibodies, when isolated from a human Fab phage library using heteroclitic peptide, fail to recognise its native peptide. We therefore argue that peptide modifications to improve antibody selections should be performed with caution as resulting antibodies, either used directly or as CARs, may lose activity towards endogenously presented tumour epitopes.

Aristotle and the Management Consultants: Shooting for Ethical Practice

The academic literature on management consulting raises many questions about the ethics of management consulting. The uncertain, emergent, and often socially constructed nature of management consultancy knowledge limits the scope both for regulating the industry in the manner of the established professions, and for evaluating management consultants’ work objectively. The character of management consultants is therefore a central issue in how far clients and other stakeholders can trust them. This paper considers three questions, using Aristotle’s Nicomachean Ethics as a guide. These are, first, ‘What is the function of a management consultant?’, second, ‘How should a management consultant act in order to be a good management consultant?’, and third, ‘Where does the boundary lie between the ethical responsibilities of the management consultant and those of the client and other stakeholders?’ Aristotelian virtue ethics are valuable in answering these questions. Their focus on character is well suited to the distinct ethical problems of management consulting. Aristotle’s overarching concern with human flourishing, and an ethically balanced approach towards benefiting from the good things to which a virtuous person may aspire, has more promise as an influence on consultants’ behaviour than the lists of prohibitions that typify codes of ethical practice in the industry. Aristotle’s call for leaders to habituate their people to ethical behaviour should be heard by the leaders of management consultancy firms. In accordance with Aristotle’s philosophy, this paper proposes a positive target at which management consultants can aim in shooting for ethical practice.

Loss of Hierarchical Control by Occasion Setters Following Lesions of the Prelimbic and Infralimbic Medial Prefrontal Cortex in Rats

Recent work suggests complementary roles of the prelimbic and infralimbic regions of the rat medial prefrontal cortex in cognitive control processes, with the prelimbic cortex implicated in top-down modulation of associations and the infralimbic cortex playing a role in the inhibition of inappropriate responses. Following selective lesions made to prelimbic or infralimbic regions (or control sham-surgery) rats received simultaneous training on Pavlovian feature negative (A+, XA−) and feature positive (B−, YB+) discriminations designed to lead to hierarchical occasion-setting control by the features (X, Y) over their respective targets (A, B). Evidence for hierarchical control was assessed in a transfer test in which features and targets were swapped (YA, XB). All groups were able to learn the feature negative and feature positive discriminations. Whilst sham-lesioned animals showed no transfer of control by features to novel targets (a hallmark of hierarchical control), rats with lesions of prelimbic or infralimbic regions showed evidence of transfer from the positive feature (Y) to the negative target (A), and from the negative feature (X) to the positive target (B; although this only achieved significance in infralimbic-lesioned animals). These data indicate that damage to either of these regions disrupts hierarchical occasion-setting control, extending our knowledge of their role in cognitive control to encompass flexible behaviours dictated by discrete cues.

Anti-BCMA BiTE® AMG 701 Potently Induces Specific T Cell Lysis of Human Multiple Myeloma (MM) Cells and Immunomodulation in the Bone Marrow Microenvironment

The first Bispecific T-cell Engager (BiTE®) targeting B-cell maturation antigen (BCMA) on multiple myeloma (MM) cells and CD3 on T cells is currently in clinical development (NCT02514239). This first-generation BiTE® has a short serum half-life and is delivered by continuous IV infusion. We here investigated the T cell-redirected cytotoxicity and immunomodulatory effects of AMG 701, a BCMA-targeting BiTE® with extended half-life, alone and in combination with lenalidomide (len), in MM cell lines and patient-derived samples. AMG 701 has a plasma half-life of 112 hr. in non-human primates (Cancer Res 2018;78(13 Suppl):Abstract nr LB-299) and is currently being evaluated clinically (NCT03287908). We here show that AMG 701 significantly induced T cell-mediated lysis of BCMA-positive MM cells resistant or sensitive to current anti-MM agents including bortezomib and lenalidomide (len). EC50 values ranged from 0.64-2.54 ng/ml following overnight treatment with AMG 701 at effector to target (E/T) ratio of 10 to 1. Moreover, following overnight treatment AMG 701-induced MM cell lysis remained robust even at low concentrations (< 2 ng/ml) and low E/T ratios (2/1, 1/2). Importantly, the presence of myeloma-supporting osteoclasts or bone marrow stromal cells did not significantly alter the ability of AMG 701 to lyse MM cells. In the presence of BCMA-positive target cells, AMG 701 rapidly induced degranulation of CD4+ and CD8+ T cells in a dose-dependent manner, evidenced by upregulated surface CD107a expression. AMG 701 triggered lysis also induced secretion of IFNγ and TNFα, to a greater extent in CD8+ than CD4+ T cell subsets. Importantly, AMG 701 (1d treatment) induced lysis of autologous patient tumor cells from relapsed and refractory MM. Combined effects of AMG 701 with len were next investigated using effector cells (PBMC or CD3+ T) pretreated with len. Len enhanced AMG 701-mediated T cell lysis of MM cells even in the presence of osteoclasts. In the presence of BCMA-positive target cells, len pretreatment also further enhanced AMG 701-induced secretion of IFNγ and TNFα from T cells, to a greater extent in CD8+ than CD4+ T cell subsets. In the absence of AMG 701, len-specific lysis of MM cells was observed, confirming len-enhanced cytotoxic potential of T cells against MM cells. We next studied the potential immunomodulatory effects of AMG 701 by flow cytometry analysis. AMG 701 was added to co-cultures of MM cells and CellTraceTM violet-labeled effector cells and T cells were analyzed at various time points. After 4d-co-incubation, AMG 701 induced more proliferation of CD8+ than CD4+ T cells (9.94% vs 0.8% at 1 ng/ml; and 47.5% vs 16.7% at 10 ng/ml, respectively). Higher levels of CD25 and CD69 were also observed in CD8+ than CD4+ T cells. Transient but not persistent upregulation of immune checkpoint molecules PD-1, TIM-3, and LAG-3 were seen on CD4+ and CD8+ T cells after coincubation with AMG 701 and BCMA-positive target cells. In parallel, the CD8+/CD4+ T cell ratios were increased (1.21 to 3.48-fold at d1 to d5, p<0.001); and further increased by 7d (1.97 to 8.64 folds at d1 to d8, p<0.001). AMG 701 induced differentiation of CD4+ and CD8+ T cells from naïve T cells to central memory (CM) and effector memory (EM) T cells, as demonstrated by changes in expression of CD62L and CD45RA. Moreover, CM and EM T cells were increased consistently after AMG 701 treatment (median % of CM+EM on CD4+ T cells: 74.8% (d1), 82.5% (d5), and 91.5% (d8), p<0.01; median % of CM+EM on CD8+ T cells: 54.4% (d1), 83.6% (d5), and 91.1% (d8), p<0.001). Furthermore, the proliferating T cells derived from AMG 701-treated co-cultures rapidly and potently lysed MM cells, even those with low levels of BCMA expression. Taken together, these results demonstrate that AMG 701 potently induces T cell-directed lysis of BCMA-positive MM cells in and triggers robust immunomodulatory effects to overcome the immunocompromised BM microenvironment. Moreover, these results provide the rationale for clinical trials based of AMG 701, alone and in combination with lenalidomide, to improve patient outcome in MM. Disclosures Munshi: OncoPep: Other: Board of director. Anderson:Bristol Myers Squibb: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; Gilead: Membership on an entity's Board of Directors or advisory committees; OncoPep: Equity Ownership, Other: Scientific founder; Millennium Takeda: Consultancy; Celgene: Consultancy.

Endermologie New Aproach in the Medicine Treatment

Using the effect of mechanical forces affecting cellular response in the treatment of post-traumatic, postoperative, post-imlantation conditions through the application of Endermologie®- mechanotransduction represents a revolutionary solution in tissue-rehabilitation and positive target tissue influencing, with faster regeneration (1). Endermologie® is a noninvasive, painless, natural method of treatments of all connective tissue transformations, muscle and circulation pathologies. The aim of our study is investigation and explanation the mechanism of action by observing the physiological effects of Endermologie® based on human studies. The paper is focused on monitoring of possitive effect tissue regeneration using endermologie as a tools mechanostimulation improvements of systems integridy and health improvement.