A disintegrin and metalloproteinases 10 and 17 modulate the immunogenicity of glioblastoma-initiating cells

Background

There are emerging reports that the family of a disintegrin and metalloproteinases (ADAM) are involved in the maintenance of the malignant phenotype of glioblastomas. Notably, ADAM proteases 10 and 17 might impair the immune recognition of glioma cells via the activating immunoreceptor NKG2D by cleavage of its ligands from the cell surface. Glioblastoma-initiating cells (GIC) with stem cell properties have been identified as an attractive target for immunotherapy. However, GIC immunogenicity seems to be low.

Methods and Results

Here,we show that ADAM10 and ADAM17 are expressed on the cell surface of GIC and contribute to an immunosuppressive phenotype by cleavage of ULBP2. The cell surface expression of ULBP2 is enhanced upon blocking ADAM10 and ADAM17, and treatment with ADAM10 and ADAM17specific inhibitors leads to enhanced immunerecognition of GIC by natural killer cells.

Conclusions

Therefore, ADAM10 and ADAM17 constitute suitable targets to boost an immune response against GIC.     

The neuropsychiatry of vitamin B12 deficiency in elderly patients

Vitamin B12 deficiency is a common cause of neuropsychiatric symptoms in elderly persons. Malabsorption accounts for the majority of cases. Vitamin B12 deficiency has been associated with neurologic, cognitive, psychotic, and mood symptoms, as well as treatment-resistance. Clinician awareness should be raised to accurately diagnose and treat early deficiencies to prevent irreversible structural brain damage, because current practice can be ineffective at identifying cases leading to neuropsychiatric sequelae. This clinical review focuses on important aspects of the recognition and treatment of vitamin B12 deficiency and neuropsychiatric manifestations of this preventable illness in elderly patients.     

Interferon‐γ down‐regulates NKG2D ligand expression and impairs the NKG2D‐mediated cytolysis of MHC class I‐deficient melanoma by natural killer cells

NKG2D operates as an activating receptor on natural killer (NK) cells and costimulates the effector function of αβ CD8⁺ T cells. Ligands of NKG2D, the MHC class I chain‐related (MIC) and UL16 binding protein (ULBP) molecules, are expressed on a variety of human tumors, including melanoma. Recent studies in mice demonstrated that NKG2D mediates tumor immune surveillance, suggesting that antitumor immunity in humans could be enhanced by therapeutic manipulation of NKG2D ligand (NKG2DL) expression. However, signals and mechanisms regulating NKG2DL expression still need to be elucidated. Here, we asked whether the proinflammatory cytokine Interferon‐γ (IFN‐γ) affects NKG2DL expression in melanoma. Cell lines, established from MHC class I‐negative and ‐positive melanoma metastases, predominantly expressed MICA and ULBP2 molecules on their surface. Upon IFN‐γ treatment, expression of MICA, in some cases, also of ULBP2 decreased. Besides melanoma, this observation was made also for glioma cells. Down‐regulation of NKG2DL surface expression was dependent on the cytokine dose and the duration of treatment, but was neither due to an intracellular retention of the molecules nor to an increased shedding of ligands from the tumor cell surface. Instead, quantitative RT‐PCR revealed a decrease of MICA‐specific mRNA levels upon IFN‐γ treatment and siRNA experiments pointed to an involvement of STAT‐1 in this process. Importantly, IFN‐γ‐treated MHC class I‐negative melanoma cells were less susceptible to NKG2D‐mediated NK cell cytotoxicity. Our study suggests that IFN‐γ, by down‐regulating ligand expression, might facilitate escape of MHC class I‐negative melanoma cells from NKG2D‐mediated killing by NK cells. © 2008 Wiley‐Liss, Inc.     

Sympathetic neurotransmission modulates expression of inflammatory markers in the rat retina

Recent evidence suggests that diabetic retinopathy may involve some components of chronic inflammation. Since surgical sympathectomy produces most of the retinal changes noted in the retina of an STZ-treated rat in a non-diabetic rat, we wanted to determine whether sympathetic neurotransmission regulates gene and protein expression of inducible nitric oxide synthase (iNOS) and the prostaglandin (PGE2) receptor, as well as the levels of PGE2. Real-time PCR was conducted on retinal samples from rats that were surgically sympathectomized to investigate steady-state mRNA expression of iNOS in the sympathectomized and contralateral retina. Western blot analysis was done on protein samples from the sympathectomized and contralateral retina for iNOS and PGE2-EP2 receptor. An ELISA assay was done on retinal supernatant fractions to measure PGE2 levels. Additionally, human retinal endothelial cells were grown in either low (5 mM) or high (25 mM) glucose medium and stimulated with isoproterenol (beta-adrenergic receptor agonist), xamoterol (beta1-adrenergic receptor subtype agonist), or BRL37344 (beta3-adrenergic receptor subtype agonist) and the effects of agonist stimulation on iNOS and PGE2 levels in low and high glucose was investigated. Sympathectomy significantly increases gene and protein expression of iNOS, as well as levels of PGE2 and protein expression of PGE2-EP2 receptor subtype. Isoproterenol treatment for 6 h to human retinal endothelial cells grown in high glucose medium reduced iNOS protein expression, but had no effect on PGE2 levels or PGE2 receptor protein expression. iNOS expression was attenutated by stimulation with xamoterol, while BRL37344 had no effect, suggesting that the iNOS effects are mediated by beta1-adrenergic receptors. These results suggest that loss of sympathetic activity, as occurs in diabetes, results in an upregulation of iNOS and PGE2-EP2 receptor protein expression, as well as PGE2 levels. Isoproterenol stimulation of human retinal endothelial cells cultured in a hyperglycemic environment decreased iNOS expression with no change in PGE2 levels, suggesting that only iNOS expression is modulated by sympathetic neurotransmission in endothelial cells. Overall, these results further the idea that alterations in sympathetic neurotransmission may result in many of the changes noted in the retina of the STZ-treated rat.     

Age-related changes in sympathetic neurotransmission in rat retina and choroid

While age-related night vision loss and age-related macular degeneration are well characterized, less is known about the normal aging process in the retina and choroid. The purpose of this study was to ascertain whether dopamine beta-hydroxylase (DBH), beta1- and beta2-adrenergic receptor gene and protein expression are altered in the retina and choroid with age. The retina and choroid were dissected from F344xBNF1 hybrid rats aged 8, 22, and 32 months. Real-time PCR and Western blot analysis were conducted to determine steady-state mRNA and protein expression. Immunohistochemistry (IHC) was conducted to localize DBH protein expression in the retina. DBH protein expression was substantially decreased with age in the retina, particularly in the outer nuclear layer, with no changes in DBH expression noted in the choroid. There was a significant increase in beta1-adrenergic receptor protein expression in retinal samples at 22 months, while beta2-adrenergic receptor protein expression was not affected by age. Decreased expression of DBH with age in the retina could lead to reduced production of norepinephrine, potentially resulting in an increase of beta1-adrenergic receptor expression due to denervation supersensitivity. Gene expression for DBH, beta1- and beta2-adrenergic receptors were observed to peak at 22 months and return to baseline levels by 32 months of age in the choroid. Our findings suggest that the retina may be more sensitive to age-related loss of sympathetic neurotransmission than the choroid, which may partially explain normal age-related vision loss in the elderly.     

High-harmonic spectroscopy of quantum phase transitions in a high-Tc superconductor

We report on the nonlinear optical signatures of quantum phase transitions in the high-temperature superconductor YBCO, observed through high harmonic generation. While the linear optical response of the material is largely unchanged when cooling across the phase transitions, the nonlinear optical response sensitively imprints two critical points, one at the critical temperature of the cuprate with the exponential growth of the surface harmonic yield in the superconducting phase and another critical point, which marks the transition from strange metal to pseudogap phase. To reveal the underlying microscopic quantum dynamics, a strong-field quasi-Hubbard model was developed, which describes the measured optical response dependent on the formation of Cooper pairs. Further, the theory provides insight into the carrier scattering dynamics and allows us to differentiate between the superconducting, pseudogap, and strange metal phases. The direct connection between nonlinear optical response and microscopic dynamics provides a powerful methodology to study quantum phase transitions in correlated materials. Further implications are light wave control over intricate quantum phases, light–matter hybrids, and application for optical quantum computing.

Attosecond technology (1), specifically the process of high harmonic generation (HHG) (2–4), provides an all-optical probe of the microscopic dynamics of atoms, molecules, and solids. Shortly after the first observation of high harmonics in atoms, their generation was understood (4–6) as arising from electron recollision after strong field photoionization and excursion in the continuum. Since the harmonic signal strongly depends on the electron recollision angle and time, high-harmonic spectroscopy (HHS) is a sensitive nonlinear probe of microscopic electronic structure with atomic spatial and suboptical cycle temporal resolution. HHS of solids (7, 8), two-dimensional materials (9, 10), or nanostructured media (11, 12) differs from the gas phase since the optical field–driven electronic wave packet is delocalized over many lattice sites, the wave function depends on the lattice momentum, and a hole has to match the electron’s momentum for recombination to occur (13, 14). Recent experimental efforts extended HHS as nonperturbative probe to quantum materials (9, 10, 15, 16) and to topological insulators (17–19). There have also been several theoretical advances, which suggest using strong fields to probe the physics of Mott insulators (20, 21), alongside the possibility of optically modifying strongly correlated matter (22) and tracking optically induced phase transitions (23), with a recent experiment reported in ref. 24.The sensitivity of HHS to the intricate microscopic details of carriers and lattice predestines HHS to investigate strong interactions and quantum correlations which lead to fascinating new states of matter such as superconductivity. The phase transition into a strongly correlated superconductive state is described by the spontaneous symmetry breaking of the U(1) redundancy when cooling below the critical temperature Tc of the material. As we will show, HHS is a sensitive probe of the dynamic evolution of the superconducting phase transition since the formation of composite bosons by pairing two fermionic spin-1/2 particles (Cooper pairs) changes the distribution of charge carriers, and this sensitively registers in the high harmonic amplitudes and spectral distribution. Pictorially, this is described in SI Appendix, Fig. S1, by a three-step model, consisting of 1) interband excitation process, 2) intraband acceleration, and 3) interband recombination. Pairing below T_c splits the bands by opening a superconducting gap Δ, and in the strongly correlated phase, the three processes of harmonic generation occur within the effective band structure for the Cooper pairs. We will also show that HHS can identify additional phase transitions between quantum phases in the strongly correlated material which are not accessible through the linear optical response, and they are difficult to detect with established methods such as superconducting quantum interference device (SQUID) magnetometry or four-probe transport measurements.A conventional superconductor can be described by the Anderson–Higgs mechanism, which explains that an optical nonlinear response is due to a gapless phase mode (Nambu–Goldstein) and a gapped amplitude mode (Higgs) of the ordering parameter. In the simplest case, and depending on the strength and type of excitation, Boltzmann and Ginzburg–Landau theories (25, 26) predict a second-order response, which mixes with the excitation mode (27, 28), thus the generation of the third harmonic (29). Unconventional high-Tc superconductors are of tremendous interest for a wide range of applications ranging from electronic devices and information processing devices to optical quantum computers and quantum simulators. However, due to their rich landscape of quantum phases and the difficulties of experimental methods to probe the microscopic dynamics, our understanding is still very limited.Among the well-established methods, e.g., transport measurements (30) or magnetic torque measurements (31, 32), photoemission measurements such as angle-resolved photoemission spectroscopy (ARPES) (33, 34) provide direct access to a material’s microscopic carrier distribution and dynamics. The interpretation of such ARPES measurement is, however, complicated by the interpretation of the bulk spectral function and the assumption of independent electron emission despite measuring a strongly correlated electronic state of matter. These are central questions to access the nature of the multibody state, which call for further developments and powerful new tools to aid in the interpretation of the physical mechanism.Therefore, the development of all-optical and ultrafast probes of the macroscopic dynamics inside such materials, which is compatible with existing methods, is highly desirable. To this aim, we apply HHS to investigate the transition between the different phases of the unconventional high-Tc superconductor YBa₂Cu₃O7−d (YBCO). We elucidate the connection between the measured optical spectra, the transition between strange metal and pseudogap phases, and the superconducting phase transition with a strong-field Hubbard model. The HHS measurement clearly shows a departure from the normal conducting phase with an increased formation of Cooper pairs upon cooling. The variation in harmonic orders is linked to phenomenological energy and phase relaxation times, which identify the transition to the fluctuation regime (35, 36), i.e., between the strange metal and pseudogap phases, and the sudden transition at Tc into the superconducting phase. Unconventional superconductors, like YBCO, are material systems in which the formation of composite bosons out of paired fermions is mediated not by phonon exchange but by some other kind of energy exchange (37), for instance, due to spin fluctuations. Such systems present many standing fascinating questions. It is thus important to have new powerful experimental techniques like HHS that provide a fresh and alternate view of the problem.     

A clinical model to predict postoperative improvement in sub-domains of the modified Japanese Orthopedic Association score for degenerative cervical myelopathy

Purpose

The modified Japanese Orthopedic Association (mJOA) score consists of six sub-domains and is used to quantify the severity of cervical myelopathy. The current study aimed to assess for predictors of postoperative mJOA sub-domains scores following elective surgical management for patients with cervical myelopathy and develop the first clinical prediction model for 12-month mJOA sub-domain scores.Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Author 1 Given name: [Byron F.] Last name [Stephens], Author 2 Given name: [Lydia J.] Last name [McKeithan], Author 3 Given name: [W. Hunter] Last name [Waddell], Author 4 Given name: [Anthony M.] Last name [Steinle], Author 5 Given name: [Wilson E.] Last name [Vaughan], Author 6 Given name: [Jacquelyn S.] Last name [Pennings], Author 7 Given name: [Jacquelyn S.] Last name [Pennings], Author 8 Given name: [Scott L.] Last name [Zuckerman], Author 9 Given name: [Kristin R.] Last name [Archer], Author 10 Given name: [Amir M.] Last name [Abtahi] Also, kindly confirm the details in the metadata are correct.Last Author listed should be Kristin R. Archer

Methods

A multivariable proportional odds ordinal regression model was developed for patients with cervical myelopathy. The model included patient demographic, clinical, and surgery covariates along with baseline sub-domain scores. The model was internally validated using bootstrap resampling to estimate the likely performance on a new sample of patients.

Results

The model identified mJOA baseline sub-domains to be the strongest predictors of 12-month scores, with numbness in legs and ability to walk predicting five of the six mJOA items. Additional covariates predicting three or more items included age, preoperative anxiety/depression, gender, race, employment status, duration of symptoms, smoking status, and radiographic presence of listhesis. Surgical approach, presence of motor deficits, number of surgical levels involved, history of diabetes mellitus, workers’ compensation claim, and patient insurance had no impact on 12-month mJOA scores.

Conclusion

Our study developed and validated a clinical prediction model for improvement in mJOA scores at 12 months following surgery. The results highlight the importance of assessing preoperative numbness, walking ability, modifiable variables of anxiety/depression, and smoking status. This model has the potential to assist surgeons, patients, and families when considering surgery for cervical myelopathy.

Level of evidence

Level III.