Preventing tumor escape by targeting a post-proteasomal trimming independent epitope

Adoptive T cell therapy (ATT) can achieve regression of large tumors in mice and humans; however, tumors frequently recur. High target peptide-major histocompatibility complex-I (pMHC) affinity and T cell receptor (TCR)-pMHC affinity are thought to be critical to preventing relapse. Here, we show that targeting two epitopes of the same antigen in the same cancer cells via monospecific T cells, which have similar pMHC and pMHC-TCR affinity, results in eradication of large, established tumors when targeting the apparently subdominant but not the dominant epitope. Only the escape but not the rejection epitope required postproteasomal trimming, which was regulated by IFN-gamma, allowing IFN-gamma-unresponsive cancer variants to evade. The data describe a novel immune escape mechanism and better define suitable target epitopes for ATT

Flux Phase as a Dynamic Jahn-Teller Phase: Berryonic Matter in the Cuprates?

There is considerable evidence for some form of charge ordering on the hole-doped stripes in the cuprates, mainly associated with the low-temperature tetragonal phase, but with some evidence for either charge density waves or a flux phase, which is a form of dynamic charge-density wave. These three states form a pseudospin triplet, demonstrating a close connection with the E X e dynamic Jahn-Teller effect, suggesting that the cuprates constitute a form of Berryonic matter. This in turn suggests a new model for the dynamic Jahn-Teller effect as a form of flux phase. A simple model of the Cu-O bond stretching phonons allows an estimate of electron-phonon coupling for these modes, explaining why the half breathing mode softens so much more than the full oxygen breathing mode. The anomalous properties of $O^{2-}$ provide a coupling (correlated hopping) which acts to stabilize density wave phases.Comment: Major Revisions: includes comparisons with specific cuprate phonon modes, 16 eps figures, revte

Increased estrogen to androgen ratio enhances immunoglobulin levels and impairs B cell function in male mice

Sex steroids, such as estrogens and androgens, are important regulators of the humoral immune response. Studies in female mice have demonstrated that alteration of circulating estrogen concentration regulates antibody-mediated immunity. As males have normally little endogenous estrogen, we hypothesized that in males high estrogens and low androgens affect the immune system and enhance the allergic inflammatory response. Here, we studied transgenic male mice expressing human aromatase (AROM+). These animals have a high circulating estrogen to androgen ratio (E/A), causing female traits such as gynecomastia. We found that AROM+ male mice had significantly higher plasma immunoglobulin levels, particularly IgE. Flow cytometry analyses of splenocytes revealed changes in mature/immature B cell ratio together with a transcriptional upregulation of the Igh locus. Furthermore, higher proliferation rate and increased IgE synthesis after IgE class-switching was found. Subsequently, we utilized an ovalbumin airway challenge model to test the allergic response in AROM+ male mice. In line with above observations, an increase in IgE levels was measured, albeit no impact on immune cell infiltration into the lungs was detected. Together, our findings suggest that high circulating E/A in males significantly alters B cell function without any significant enhancement in allergic inflammation.</p

Matter rogue wave in Bose-Einstein condensates with attractive atomic interaction

We investigate the matter rogue wave in Bose-Einstein Condensates with attractive interatomic interaction analytically and numerically. Our results show that the formation of rogue wave is mainly due to the accumulation of energy and atoms toward to its central part; Rogue wave is unstable and the decay rate of the atomic number can be effectively controlled by modulating the trapping frequency of external potential. The numerical simulation demonstrate that even a small periodic perturbation with small modulation frequency can induce the generation of a near-ideal matter rogue wave. We also give an experimental protocol to observe this phenomenon in Bose-Einstein Condensates

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

The quest for CD8⁺ memory stem cells.

In this issue of Immunity, Turtle et al. (2009) describe the identification of a distinct CD8(+) memory T cell subset in humans, which could bring us closer to the identification of the enigmatic "memory stem cell.

Managing tight-binding receptors for new separations technologies. 1998 annual progress report

'Whereas such traditional separation methodologies as ion exchange and solvent extraction require rapid interaction between ligands and metal ions, the most strongly binding ligands invariably bind slowly; e.g., cryptates bind and dissociate more slowly than macrocycles, which are slower than open-chain chelating ligands. This project seeks to maximize the binding and dissociation rates for tight-binding receptors in order to make them more useful to separations science. An alternative slow-binding technology is also under exploration.

Whole-body anatomy of human T cells.

Knowledge of the regional tissue distribution of T&nbsp;cell subsets is a prerequisite for understanding protective immunity and the pathophysiology of T&nbsp;cell-mediated diseases. In this issue of Immunity, Sathaliyawala et&nbsp;al. (2012) present a comprehensive human tissue T&nbsp;cell analysis

The smallest unit: Effector and memory CD8⁺ T cell differentiation on the single cell level.

CD8(+) T cell immune responses provide immediate protection against primary infection and durable memory capable of rapidly fighting off re-infection. Immediate protection and lasting memory are implemented by phenotypically and functionally distinct T cell subsets. While it is now widely accepted that these diverge from a common source of na&iuml;ve T cells (T(n)), the developmental relation and succession of effector and memory T cell subsets is still under intense debate. Recently, a distinct memory T cell subset has been suggested to possess stem cell-like features, sparking the hope to harness its capacity for self-renewal and diversification for successful therapy of chronic infections or malignant diseases. In this review we highlight current developmental models of memory generation, T cell subset diversification and T cell stemness. We discuss the importance of single cell monitoring techniques for adequately mapping these developmental processes and take a brief look at signaling components active in the putative stem cell-like memory T cell compartment