Some forms of chemotherapy can enhance antitumor immunity through immunogenic cell death, resulting in increased T-cell activation and tumor infiltration. Such effects could potentially sensitize ...tumors to immunotherapies, including checkpoint blockade. We investigated whether platinum- and taxane-based chemotherapy for ovarian cancer induces immunologic changes consistent with this possibility.
Matched pre- and post-neoadjuvant chemotherapy tumor samples from 26 high-grade serous carcinoma (HGSC) patients were analyzed by immunohistochemistry (IHC) for a large panel of immune cells and associated factors. The prognostic significance of post-chemotherapy TIL patterns was assessed in an expanded cohort (
= 90).
Neoadjuvant chemotherapy was associated with increased densities of CD3
, CD8
, CD8
TIA-1
, PD-1
and CD20
TIL. Other immune subsets and factors were unchanged, including CD79a
CD138
plasma cells, CD68
macrophages, and MHC class I on tumor cells. Immunosuppressive cell types were also unchanged, including FoxP3
PD-1
cells (putative regulatory T cells), IDO-1
cells, and PD-L1
cells (both macrophages and tumor cells). Hierarchical clustering revealed three response patterns: (i) TIL
tumors showed increases in multiple immune markers after chemotherapy; (ii) TIL
tumors underwent similar increases, achieving patterns indistinguishable from the first group; and (iii) TIL
cases generally remained negative. Despite the dramatic increases seen in the first two patterns, post-chemotherapy TIL showed limited prognostic significance.
Chemotherapy augments pre-existing TIL responses but fails to relieve major immune-suppressive mechanisms or confer significant prognostic benefit. Our findings provide rationale for multipronged approaches to immunotherapy tailored to the baseline features of the tumor microenvironment.
.
The beneficial uptake of nutrients by wetland plants is countered to some extent by nutrient release back into the aquatic environment due to vegetative die-back. This current study examined whether
...Leersia oryzoides, a common wetland plant, exhibits luxury uptake of nutrients from simulated farm runoff. The study also tested whether with subsequent decomposition, these nutrients are released back into the water column. When exposed to elevated (>2
mg/L N and P) runoff,
L. oryzoides assimilated significantly higher concentrations of nitrogen (
p
<
0.001) and phosphorus (
p
<
0.001) in above-ground biomass as compared to non-enriched treatments (<0.05
mg/L N and P). Subsequently, senescence of enriched above-ground biomass yielded significantly higher concentrations of phosphorus (2.19
±
0.84
mg P/L). Using
L. oryzoides as our model, this study demonstrates nitrogen and phosphorus sequestration during the growing season and release of phosphorus in the winter.
Release of sequestered nutrients during plant senescence.
Cancers accumulate mutations over time, each of which brings the potential for recognition by the immune system. We evaluated T-cell recognition of the tumor mutanome in patients with ovarian cancer ...undergoing standard treatment.
Tumor-associated T cells from 3 patients with ovarian cancer were assessed by ELISPOT for recognition of nonsynonymous mutations identified by whole exome sequencing of autologous tumor. The relative levels of mutations and responding T cells were monitored in serial tumor samples collected at primary surgery and first and second recurrence.
The vast majority of mutations (78/79) were not recognized by tumor-associated T cells; however, a highly specific CD8(+) T-cell response to the mutation hydroxysteroid dehydrogenase-like protein 1 (HSDL1)(L25V) was detected in one patient. In the primary tumor, the HSDL1(L25V) mutation had low prevalence and expression, and a corresponding T-cell response was undetectable. At first recurrence, there was a striking increase in the abundance of the mutation and corresponding MHC class I epitope, and this was accompanied by the emergence of the HSDL1(L25V)-specific CD8(+) T-cell response. At second recurrence, the HSDL1(L25V) mutation and epitope continued to be expressed; however, the corresponding T-cell response was no longer detectable.
The immune system can respond to the evolving ovarian cancer genome. However, the T-cell response detected here was rare, was transient, and ultimately failed to prevent disease progression. These findings reveal the limitations of spontaneous tumor immunity in the setting of standard treatments and suggest a high degree of ignorance of tumor mutations that could potentially be reversed by immunotherapy.
We address here the role of CD4 T cell cooperation in the activation of CD4 T cells. Administration of aggregated hen egg lysozyme (HEL) without microbial adjuvant to BALB/c mice normally generates ...cytokine-producing CD4 T cells specific for the HEL major peptide, HEL105–120, as well as CD4 T cells specific for HEL non-major peptides. The prior administration of HEL105–120 ablates the generation of cytokine-secreting CD4 T cells specific for HEL105–120, as well as the CD4 T cells specific for HEL non-major peptides, normally generated upon HEL challenge. Thus, the activation of HEL non-major peptide-specific CD4 T cells appears to depend upon the HEL105–120-specific CD4 T cell population. In contrast, when HEL105–120 and saline-treated mice are challenged with HEL coupled to ovalbumin (OVA), CD4 T cell responses to HEL non-major peptides and to OVA are the same, whereas treated mice still do not generate cytokine-secreting cells specific for HEL105–120. We infer that the administration of HEL105–120 does not generate regulatory cells capable of down-regulating CD4 T cell responses to HEL and OVA peptides. OVA-specific CD4 T cells restore the generation of HEL non-major peptide-specific T cells in the absence of HEL major peptide-specific T cells. We conclude that the generation of CD4 T cells producing IL-2, IFN-γ and IL-4 requires CD4 T cell cooperation and that this cooperation is not mediated simply by CD40–CD40L interactions. We also conclude from these observations that there is no requirement for a microbial or danger signal for CD4 T cell activation.
Texture Effects in IrMn/CoFe Exchange Bias Systems Aley, N.P.; Vallejo-Fernandez, G.; Kroeger, R. ...
IEEE transactions on magnetics,
11/2008, Letnik:
44, Številka:
11
Journal Article, Conference Proceeding
We report an enhancement of the average blocking temperature <T B > in IrMn/CoFe exchange bias systems due to an increase in the anisotropy constant of the IrMn. This is related to a (111) texture of ...IrMn parallel to the interface. Si /Seed (5 nm)/IrMn (10 nm)/CoFe (3 nm)/Ta (10 nm) were prepared by dc sputtering. Cu, Ru, and NiCr seed layers were used. X-ray diffraction studies involving both thetas/2thetas and grazing incidence scans revealed a strong (111) texture of the IrMn parallel to the interface for the samples with a NiCr seed layer. Cu and Ru seed layers did not cause a marked texture. Thermal activation measurements found an enhancement of the average blocking temperature from 367 K for the sample with Cu seed layer to 477 K for the sample with a NiCr seed. The anisotropy constant was found to increase from (2.8plusmn0.2) times 10 6 erg/cm 3 for the sample with a Cu seed layer to (3.3 plusmn 0.4) times 10 7 erg/cm 3 for the sample with a NiCr seed layer. We find that the increase in the anisotropy constant leads to an enhanced blocking temperature.
Many observations bear upon the cellular and molecular requirements for CD4 T cell activation. The interaction of CD4 T cells with dendritic cells (DC), central to the induction of most immune ...responses, is the most studied. However, leukocytes other than DC can dramatically affect the induction and differentiation of CD4 T cells into effector cells. We recently provided indirect evidence that in vivo CD4 T cooperation facilitates the activation of CD4 T cells. Here, we demonstrate that the activation of CD4 T cells, specific for the hen egg lysozyme (HEL)(105) (-120) peptide, is optimally achieved when BALB/c mice are immunized with additional MHC class II-binding HEL peptides in incomplete Freund's adjuvant. This cooperation cannot be mimicked by the coadministration of LPS or of an agonistic antibody to CD40, at the time of immunization. In contrast, OX40-OX40L interactions are necessary for CD4 T cell cooperation in that an OX40 agonistic antibody can replace, and an OX40L-blocking antibody can abrogate, CD4 T cell cooperation in situations where such cooperation would otherwise enhance the activation of CD4 T cells.
How do educators enhance their global competencies and intercultural communication skills so they can better educate students in our increasingly diverse society? In Spring 2000, the authors ...conducted a survey of 52 New Jersey City University faculty and staff to assess the relationships between their international experience, global competencies, and levels of intercultural sensitivity. The survey drew on Milton Bennett’s Developmental Model of Intercultural Sensitivity and definitions of global competency from Wilson, Stohl, Singer, and Hanvey. The authors of this article found that both second-language proficiency and substantive experience abroad independently increase the likelihood that an educator will be more advanced on the Bennett Intercultural Sensitivity Scale. This survey provides directional information about the relationship between second-language acquisition, experience abroad, and ethnorelativism. The findings suggest that we need global, intercultural, and professional development for faculty and staff that is ongoing, substantial, and inclusive of work in another language and culture.
The advent of highly segmented gamma-ray detectors with good energy resolution has made a new class of gamma-ray detectors possible. These instruments record the positions and energies of each ...individual gamma-ray interaction with high precision. Analysis of the individual interactions can provide energy and directional information, even for events with only partial energy deposition. Advantages over traditional gamma-ray detectors include enhanced efficiency, background rejection, gamma-ray imaging, and sensitivity to polarization. Consider those gamma-rays that interact three or more times in the detector. The energy of the gamma-ray that initiated one of these events is uniquely determined by measuring the energies of the first two interactions and the scatter angle of the second interaction. The precision of this measurement is limited by the energy and position resolution of the detector, but also from Doppler broadening that results from gamma-ray scattering off-bound electrons in the detector. It is also essential to correctly sequence the first three interactions. The importance of Doppler broadening is greater in higher Z-materials, thus silicon becomes a good choice for the detector material. We discuss performance and simulations of the multiple Compton telescope. Possible applications include an advanced Compton telescope (ACT) for astrophysics, a medical multiple-gamma detector high-energy imaging survey instrument, and a gamma-ray tracking detector for future low-energy nuclear physics experiments.
Increased focus is being placed on the ability of native vegetation to mitigate potential harmful effects of agricultural runoff, especially pyrethroid insecticides. Replicate 379 L Rubbermaid tubs ...(1.25 m l x 0.6 m w x 0.8 m h) were planted with individual species of cutgrass (Leersia oryzoides), cattails (Typha latifolia), bur-reed (Sparganium americanum), and powdery alligator-flag (Thalia dealbata), all common wetland macrophytes found in the Mississippi Delta, USA, agricultural region. Permethrin-enriched water (target concentration, 5 μg L⁻¹) was pumped in at a 4-h hydraulic retention time at one end of the tub and discharged at the far end. Water samples were collected from discharge at 1-h intervals for 12 h and analyzed for permethrin concentrations. Permethrin removal rates were compared for the four different plant treatments and nonvegetated sediment-water controls. Results indicated that no particular single plant species was more effective at removing permethrin in water relative to unplanted controls. Overall mass reductions (from inflow to outflow) for cis-permethrin ranged from 67% ± 6% in T. latifolia to 71% ± 2% in L. oryzoides. The trans-permethrin overall mass reductions ranged from 76% ± 4% in S. americanum to 82% ± 2% in the unplanted control. Sediment and plant samples collected at the study conclusion indicated that 77%-95% of measured permethrin mass was associated with sediment for mesocosms planted with L. oryzoides, T. latifolia, and T. dealbata. Conversely, mesocosms planted with S. americanum had 83% of measured mass associated with the plant material. Specific plant-pesticide retention studies can lead to improved planning for best management practices and remediation techniques such as constructed wetlands and vegetated agricultural drainage ditches.
PDF
