Exploiting Human NK Cells in Tumor Therapy

NK cells play an important role in the innate defenses against tumor growth and metastases. Human NK cell activation and function are regulated by an array of HLA class I-specific inhibitory receptors and activating receptors recognizing ligands expressed de novo on tumor or virus-infected cells. NK cells have been exploited in immunotherapy of cancer, including: (1) the in vivo infusion of IL-2 or IL-15, cytokines inducing activation and proliferation of NK cells that are frequently impaired in cancer patients. Nonetheless, the significant toxicity experienced, primarily with IL-2, limited their use except for combination therapies, e.g., IL-15 with checkpoint inhibitors; (2) the adoptive immunotherapy with cytokine-induced NK cells had effect on some melanoma metastases (lung), while other localizations were not affected; (3) a remarkable evolution of adoptive cell therapy is represented by NK cells engineered with CAR-targeting tumor antigens (CAR-NK). CAR-NK cells complement CAR-T cells as they do not cause GvHD and may be obtained from unrelated donors. Accordingly, CAR-NK cells may represent an \u201coff-the-shelf\u201d tool, readily available for effective tumor therapy; (4) the efficacy of adoptive cell therapy in cancer is also witnessed by the \u3b1\u3b2T cell- and B cell-depleted haploidentical HSC transplantation in which the infusion of donor NK cells and \u3b3\u3b4T cells, together with HSC, sharply reduces leukemia relapses and infections; (5) a true revolution in tumor therapy is the use of mAbs targeting checkpoint inhibitors including PD-1, CTLA-4, the HLA class I-specific KIR, and NKG2A. Since PD-1 is expressed not only by tumor-associated T cells but also by NK cells, its blocking might unleash NK cells playing a crucial effector role against HLA class I-deficient tumors that are undetectable by T cells

Human γδ T-Cells: from surface receptors to the therapy of high-risk leukemias

γδ T lymphocytes are potent effector cells, capable of efficiently killing tumor and leukemia cells. Their activation is mediated by γδ T-cell receptor (TCR) and by activating receptors shared with NK cells (e.g., NKG2D and DNAM-1). γδ T-cell triggering occurs upon interaction with specific ligands, including phosphoantigens (for Vγ9Vδ2 TCR), MICA-B and UL16 binding protein (for NKG2D), and PVR and Nectin-2 (for DNAM-1). They also respond to cytokines undergoing proliferation and release of cytokines/chemokines. Although at the genomic level γδ T-cells have the potential of an extraordinary TCR diversification, in tissues they display a restricted repertoire. Recent studies have identified various γδ TCR rearrangements following either hematopoietic stem cell transplantation (HSCT) or cytomegalovirus infection, accounting for their "adaptive" potential. In humans, peripheral blood γδ T-cells are primarily composed of Vγ9Vδ2 chains, while a minor proportion express Vδ1. They do not recognize antigens in the context of MHC molecules, thus bypassing tumor escape based on MHC class I downregulation. In view of their potent antileukemia activity and absence of any relevant graft-versus-host disease-inducing effect, γδ T-cells may play an important role in the successful clinical outcome of patients undergoing HLA-haploidentical HSCT depleted of TCR αβ T/CD19+ B lymphocytes to cure high-risk acute leukemias. In this setting, high numbers of both γδ T-cells (Vδ1 and Vδ2) and NK cells are infused together with CD34+ HSC and may contribute to rapid control of infections and leukemia relapse. Notably, zoledronic acid potentiates the cytolytic activity of γδ T-cells in vitro and its infusion in patients strongly promotes γδ T-cell differentiation and cytolytic activity; thus, treatment with this agent may contribute to further improve the patient clinical outcome after HLA-haploidentical HSCT depleted of TCR αβ T/CD19+ B lymphocytes

Trojan Horse as an indirect technique in nuclear astrophysics. Resonance reactions

The Trojan Horse method is a powerful indirect technique that provides information to determine astrophysical factors for binary rearrangement processes $x + A \to b + B$ at astrophysically relevant energies by measuring the cross section for the Trojan Horse reaction $a + A \to y+ b + B$ in quasi-free kinematics. We present the theory of the Trojan Horse method for resonant binary subreactions based on the half-off-energy-shell R matrix approach which takes into account the off-energy-shell effects and initial and final state interactions.Comment: 6 pages and 1 figur

Solving the large discrepancy between inclusive and exclusive measurements of the 8Li+4He→11B+n{}^8{\rm Li}+{}^4{\rm He}\to{}^{11}{\rm B}+n reaction cross section at astrophysical energies

A solution of the large discrepancy existing between inclusive and exclusive measurements of the ${}^8{\rm Li}+{}^4{\rm He}\to{}^{11}{\rm B}+n$ reaction cross section at $E_{cm} <3$ MeV is evaluated. This problem has profound astrophysical relevance for this reaction is of great interest in Big-Bang and r-process nucleosynthesis. By means of a novel technique, a comprehensive study of all existing ${}^8{\rm Li}+{}^4{\rm He}\to{}^{11}{\rm B}+n$ cross section data is carried out, setting up a consistent picture in which all the inclusive measurements provide the reliable value of the cross section. New unambiguous signatures of the strong branch pattern non-uniformities, near the threshold of higher ${}^{11}{\rm B}$ excited levels, are presented and their possible origin, in terms of the cluster structure of the involved excited states of ${}^{11}{\rm B}$ and ${}^{12}{\rm B}$ nuclei, is discussed.Comment: 5 pages, 4 figures, 1 tabl

Molecular Structures in T=1 states of 10B

Multi-center (molecular) structures can play an important role in light nuclei. The highly deformed rotational band in 10Be with band head at 6.179 MeV has been observed recently and suggested to have an exotic alpha:2n:alpha configuration. A search for states with alpha:pn:alpha two-center molecular configurations in 10B that are analogous to the states with alpha:2n:alpha structure in 10Be has been performed. The T=1 isobaric analog states in 10B were studied in the excitation energy range of E=8.7-12.1 MeV using the reaction 1H(9Be,alpha)6Li*(T=1, 0+, 3.56 MeV). An R-matrix analysis was used to extract parameters for the states observed in the (p,alpha) excitation function. Five T=1 states in 10B have been identified. The known 2+ and 3- states at 8.9 MeV have been observed and their partial widths have been measured. The spin-parities and partial widths for three higher lying states were determined. Our data support theoretical predictions that the 2+ state at 8.9 MeV (isobaric analog of the 7.54 MeV state in 10Be) is a highly clustered state and can be identified as a member of the alpha:np:alpha rotational band. The next member of this band, the 4+ state, has not been found. A very broad 0+ state at 11 MeV that corresponds to pure alpha+6Li(0+,T=1) configuration is suggested and it might be related to similar structures found in 12C, 18O and 20Ne.Comment: 10 pages, 10 figures, accepted in Physical Review

Epigenome-wide association study reveals decreased average methylation levels years before breast cancer diagnosis

Interest in the potential of DNA methylation in peripheral blood as a biomarker of cancer risk is increasing. We aimed to assess whether epigenome-wide DNA methylation measured in peripheral blood samples obtained before onset of the disease is associated with increased risk of breast cancer. We report on three independent prospective nested case-control studies from the European Prospective Investigation into Cancer and Nutrition (EPIC-Italy; n = 162 matched case-control pairs), the Norwegian Women and Cancer study (NOWAC; n = 168 matched pairs), and the Breakthrough Generations Study (BGS; n = 548 matched pairs). We used the Illumina 450k array to measure methylation in the EPIC and NOWAC cohorts. Whole-genome bisulphite sequencing (WGBS) was performed on the BGS cohort using pooled DNA samples, combined to reach 50× coverage across ~16 million CpG sites in the genome including 450k array CpG sites. Mean β values over all probes were calculated as a measurement for epigenome-wide methylation

Scanning tunneling microscopy and Raman spectroscopy of polymeric sp-sp2 carbon atomic wires synthesized on the Au(111) surface

Long linear carbon nanostructures based on sp-hybridization can be synthesized by exploiting on-surface synthesis of halogenated precursors evaporated on Au(111), thus opening a way to investigations by surface-science techniques. By means of an experimental approach combining scanning tunneling microscopy and spectroscopy (STM and STS) with ex situ Raman spectroscopy we investigate the structural, electronic and vibrational properties of polymeric sp-sp2 carbon atomic wires composed by sp-carbon chains connected through phenyl groups. Density-functional-theory (DFT) calculations of the structure and the electronic density of states allow us to simulate STM images and to compute Raman spectra. The comparison of experimental data with DFT simulations unveil the properties and the formation stages as a function of the annealing temperature. Atomic-scale structural information from STM complement the Raman sensitivity to the single molecular bond to open the way to detailed understanding of these novel carbon nanostructures

Bias in protein and potassium intake collected with 24-h recalls (EPIC-Soft) is rather comparable across European populations

Purpose: We investigated whether group-level bias of a 24-h recall estimate of protein and potassium intake, as compared to biomarkers, varied across European centers and whether this was influenced by characteristics of individuals or centers. Methods: The combined data from EFCOVAL and EPIC studies included 14 centers from 9 countries (n = 1,841). Dietary data were collected using a computerized 24-h recall (EPIC-Soft). Nitrogen and potassium in 24-h urine collections were used as reference method. Multilevel linear regression analysis was performed, including individual-level (e.g., BMI) and center-level (e.g., food pattern index) variables. Results: For protein intake, no between-center variation in bias was observed in men while it was 5.7% in women. For potassium intake, the between-center variation in bias was 8.9% in men and null in women. BMI was an important factor influencing the biases across centers (p <0.01 in all analyses). In addition, mode of administration (p = 0.06 in women) and day of the week (p = 0.03 in men and p = 0.06 in women) may have influenced the bias in protein intake across centers. After inclusion of these individual variables, between-center variation in bias in protein intake disappeared for women, whereas for potassium, it increased slightly in men (to 9.5%). Center-level variables did not influence the results. Conclusion: The results suggest that group-level bias in protein and potassium (for women) collected with 24-h recalls does not vary across centers and to a certain extent varies for potassium in men. BMI and study design aspects, rather than center-level characteristics, affected the biases across center

Human Zika infection induces a reduction of IFN-γ producing CD4 T-cells and a parallel expansion of effector Vδ2 T-cells

The definition of the immunological response to Zika (ZIKV) infection in humans represents a key issue to identify protective profile useful for vaccine development and for pathogenesis studies. No data are available on the cellular immune response in the acute phase of human ZIKV infection, and its role in the protection and/or pathogenesis needs to be clarified. We studied and compared the phenotype and functionality of T-cells in patients with acute ZIKV and Dengue viral (DENV) infections. A significant activation of T-cells was observed during both ZIKV and DENV infections. ZIKV infection was characterized by a CD4 T cell differentiation toward effector cells and by a lower frequency of IFN-γ producing CD4 T cells. Moreover, a substantial expansion of CD3+CD4−CD8− T-cell subset expressing Vδ2 TCR was specifically observed in ZIKV patients. Vδ2 T cells presented a terminally differentiated profile, expressed granzyme B and maintained their ability to produce IFN-γ. These findings provide new knowledge on the immune response profile during self-limited infection that may help in vaccine efficacy definition, and in identifying possible immuno-pathogenetic mechanisms of severe infection