Targeting the immune checkpoint pathway has demonstrated antitumor cytotoxicity in treatment-refractory head and neck squamous cell carcinoma (HNSC). To understand the molecular mechanisms ...underpinning its antitumor response, we characterized the immune landscape of HNSC by their tumor and stromal compartments to identify novel immune molecular subgroups.
A training cohort of 522 HNSC samples from the Cancer Genome Atlas profiled by RNA sequencing was analyzed. We separated gene expression patterns from tumor, stromal, and immune cell gene using a non-negative matrix factorization algorithm. We correlated the expression patterns with a set of immune-related gene signatures, potential immune biomarkers, and clinicopathological features. Six independent datasets containing 838 HNSC samples were used for validation.
Approximately 40% of HNSCs in the cohort (211/522) were identified to show enriched inflammatory response, enhanced cytolytic activity, and active interferon-γ signaling (all, P < 0.001). We named this new molecular class of tumors the Immune Class. Then we found it contained two distinct microenvironment-based subtypes, characterized by markers of active or exhausted immune response. The Exhausted Immune Class was characterized by enrichment of activated stroma and anti-inflammatory M2 macrophage signatures, WNT/transforming growth factor-β signaling pathway activation and poor survival (all, P < 0.05). An enriched proinflammatory M1 macrophage signature, enhanced cytolytic activity, abundant tumor-infiltrating lymphocytes, high human papillomavirus (HPV) infection, and favorable prognosis were associated with Active Immune Class (all, P < 0.05). The robustness of these immune molecular subgroups was verified in the validation cohorts, and Active Immune Class showed potential response to programmed cell death-1 blockade (P = 0.01).
This study revealed a novel Immune Class in HNSC; two subclasses characterized by active or exhausted immune responses were also identified. These findings provide new insights into tailoring immunotherapeutic strategies for different HNSC subgroups.
Transcatheter aortic valve replacement (TAVR) indications are expanding, leading to an increasing number of patients with bicuspid aortic stenosis undergoing TAVR. Pivotal randomized trials conducted ...to obtain US Food and Drug Administration approval excluded bicuspid anatomy.
To compare the outcomes of TAVR with a balloon-expandable valve for bicuspid vs tricuspid aortic stenosis.
Registry-based prospective cohort study of patients undergoing TAVR at 552 US centers. Participants were enrolled in the Society of Thoracic Surgeons (STS)/American College of Cardiology (ACC) Transcatheter Valve Therapies Registry from June 2015 to November 2018.
TAVR for bicuspid vs tricuspid aortic stenosis.
Primary outcomes were 30-day and 1-year mortality and stroke. Secondary outcomes included procedural complications, valve hemodynamics, and quality of life assessment.
Of 81 822 consecutive patients with aortic stenosis (2726 bicuspid; 79 096 tricuspid), 2691 propensity-score matched pairs of bicuspid and tricuspid aortic stenosis were analyzed (median age, 74 years interquartile range {IQR}, 66-81 years; 39.1%, women; mean SD STS-predicted risk of mortality, 4.9% 4.0% and 5.1% 4.2%, respectively). All-cause mortality was not significantly different between patients with bicuspid and tricuspid aortic stenosis at 30 days (2.6% vs 2.5%; hazard ratio HR, 1.04, 95% CI, 0.74-1.47) and 1 year (10.5% vs 12.0%; HR, 0.90 95% CI, 0.73-1.10). The 30-day stroke rate was significantly higher for bicuspid vs tricuspid aortic stenosis (2.5% vs 1.6%; HR, 1.57 95% CI, 1.06-2.33). The risk of procedural complications requiring open heart surgery was significantly higher in the bicuspid vs tricuspid cohort (0.9% vs 0.4%, respectively; absolute risk difference RD, 0.5% 95% CI, 0%-0.9%). There were no significant differences in valve hemodynamics. There were no significant differences in moderate or severe paravalvular leak at 30 days (2.0% vs 2.4%; absolute RD, 0.3% 95% CI, -1.3% to 0.7%) and 1 year (3.2% vs 2.5%; absolute RD, 0.7% 95% CI, -1.3% to 2.7%). At 1 year there was no significant difference in improvement in quality of life between the groups (difference in improvement in the Kansas City Cardiomyopathy Questionnaire overall summary score, -2.4 95% CI, -5.1 to 0.3; P = .08).
In this preliminary, registry-based study of propensity-matched patients who had undergone transcatheter aortic valve replacement for aortic stenosis, patients with bicuspid vs tricuspid aortic stenosis had no significant difference in 30-day or 1-year mortality but had increased 30-day risk for stroke. Because of the potential for selection bias and the absence of a control group treated surgically for bicuspid stenosis, randomized trials are needed to adequately assess the efficacy and safety of transcatheter aortic valve replacement for bicuspid aortic stenosis.
Organic semiconductors have great potential as the active material in low-cost, large area plastic electronics, whether as light-emitting diodes (LEDs), field-effect transistors (FETs) or solar ...cells. Organic semiconducting materials retain the processability associated with polymers while maintaining good optoelectronic properties, for example, high absorption coefficients for photons in the visible, and field-effect mobilities comparable with that of amorphous silicon. The elucidation of important structure−property relationships is vital for the design of functional, high-performance organic semiconductors. In this short review, we summarize such relationships stemming from the halogenation of organic semiconductors. While it has been known in the past decade that fluorination lowers the energy levels in carbon based systems, induces stability and electron transport, less is known about the effect of the other halogens. Chlorination has recently been shown to be a viable route to n-type materials. The bandgap of conjugated compounds can also be decreased slightly by the addition of Cl, Br, and I to the aromatic core. The effect of the halogenated moieties on the packing of molecules is discussed.
We report the updated classification of primary immunodeficiencies compiled by the Primary Immunodeficiency Expert Committee (PID EC) of the International Union of Immunological Societies (IUIS). In ...the two years since the previous version, 34 new gene defects are reported in this updated version. For each disorder, the key clinical and laboratory features are provided. In this new version we continue to see the increasing overlap between immunodeficiency, as manifested by infection and/or malignancy, and immune dysregulation, as manifested by auto-inflammation, auto-immunity, and/or allergy. There is also an increased number of genetic defects that lead to susceptibility to specific organisms which reflects the finely tuned nature of immune defense systems. This classification is the most up to date catalogue of all known and published primary immunodeficiencies and acts as a current reference of the knowledge of these conditions and is an important aid for the genetic and molecular diagnosis of patients with these rare diseases.
The culture of bone marrow derived mesenchymal stem cells (MSCs), as well as the control of its differentiation toward different tissue lineage, is a very important part of tissue engineering, where ...cells are combined with artificial scaffold to regenerate tissues. Graphene (G) and graphene oxide (GO) sheets are soft membranes with high in-plane stiffness and can potentially serve as a biocompatible, transferable, and implantable platform for stem cell culture. While the healthy proliferation of stem cells on various carbon platforms has been demonstrated, the chemical role of G and GO, if any, in guiding uncommitted stem cells toward differentiated cells is not known. Herein, we report that the strong noncovalent binding abilities of G allow it to act as a preconcentration platform for osteogenic inducers, which accelerate MSCs growing on it toward the osteogenic lineage. The molecular origin of accelerated differentation is investigated by studying the binding abilities of G and GO toward different growth agents. Interestingly, differentiation to adipocytes is greatly suppressed on G because insulin, which is a key regulator for the synthesis of fatty acids, is denatured upon π–π adsorption on G; in contrast, GO does not interfere with adipogenesis due to electrostatic binding with insulin. The different binding interactions and their subsequent influence on stem cell growth and differentiation are ascribed to different degrees of π–π stacking and electrostatic and hydrogen bonding mediated by G and GO.
Food allergy: is prevalence increasing? Tang, Mimi L. K.; Mullins, Raymond J.
Internal medicine journal,
March 2017, 2017-Mar, 2017-03-00, 20170301, Volume:
47, Issue:
3
Journal Article
Peer reviewed
Open access
It is generally accepted that the prevalence of food allergy has been increasing in recent decades, particularly in westernised countries, yet high‐quality evidence that is based on challenge ...confirmed diagnosis of food allergy to support this assumption is lacking because of the high cost and potential risks associated with conducting food challenges in large populations. Accepting this caveat, the use of surrogate markers for diagnosis of food allergy (such as nationwide data on hospital admissions for food anaphylaxis or clinical history in combination with allergen‐specific IgE (sIgE) measurement in population‐based cohorts) has provided consistent evidence for increasing prevalence of food allergy at least in western countries, such as the UK, United States and Australia. Recent reports that children of East Asian or African ethnicity who are raised in a western environment (Australia and United States respectively) have an increased risk of developing food allergy compared with resident Caucasian children suggest that food allergy might also increase across Asian and African countries as their economies grow and populations adopt a more westernised lifestyle. Given that many cases of food allergy persist, mathematical principles would predict a continued increase in food allergy prevalence in the short to medium term until such time as an effective treatment is identified to allow the rate of disease resolution to be equal to or greater than the rate of new cases.
The 3' poly(A) tail of messenger RNA is fundamental to regulating eukaryotic gene expression. Shortening of the poly(A) tail, termed deadenylation, reduces transcript stability and inhibits ...translation. Nonetheless, the mechanism for poly(A) recognition by the conserved deadenylase complexes Pan2-Pan3 and Ccr4-Not is poorly understood. Here we provide a model for poly(A) RNA recognition by two DEDD-family deadenylase enzymes, Pan2 and the Ccr4-Not nuclease Caf1. Crystal structures of Saccharomyces cerevisiae Pan2 in complex with RNA show that, surprisingly, Pan2 does not form canonical base-specific contacts. Instead, it recognizes the intrinsic stacked, helical conformation of poly(A) RNA. Using a fully reconstituted biochemical system, we show that disruption of this structure-for example, by incorporation of guanosine into poly(A)-inhibits deadenylation by both Pan2 and Caf1. Together, these data establish a paradigm for specific recognition of the conformation of poly(A) RNA by proteins that regulate gene expression.
Gene-gene interactions have long been recognized to be fundamentally important for understanding genetic causes of complex disease traits. At present, identifying gene-gene interactions from ...genome-wide case-control studies is computationally and methodologically challenging. In this paper, we introduce a simple but powerful method, named “BOolean Operation-based Screening and Testing” (BOOST). For the discovery of unknown gene-gene interactions that underlie complex diseases, BOOST allows examination of all pairwise interactions in genome-wide case-control studies in a remarkably fast manner. We have carried out interaction analyses on seven data sets from the Wellcome Trust Case Control Consortium (WTCCC). Each analysis took less than 60 hr to completely evaluate all pairs of roughly 360,000 SNPs on a standard 3.0 GHz desktop with 4G memory running the Windows XP system. The interaction patterns identified from the type 1 diabetes data set display significant difference from those identified from the rheumatoid arthritis data set, although both data sets share a very similar hit region in the WTCCC report. BOOST has also identified some disease-associated interactions between genes in the major histocompatibility complex region in the type 1 diabetes data set. We believe that our method can serve as a computationally and statistically useful tool in the coming era of large-scale interaction mapping in genome-wide case-control studies.
Nanoceria or cerium oxide nanoparticles characterised by the co-existing of Ce
3+
and Ce
4+
that allows self-regenerative, redox-responsive dual-catalytic activities, have attracted interest as an ...innovative approach to treating cancer. Depending on surface characteristics and immediate environment, nanoceria exerts either anti- or pro-oxidative effects which regulate reactive oxygen species (ROS) levels in biological systems. Nanoceria mimics ROS-related enzymes that protect normal cells at physiological pH from oxidative stress and induce ROS production in the slightly acidic tumour microenvironment to trigger cancer cell death. Nanoceria as nanozymes also generates molecular oxygen that relieves tumour hypoxia, leading to tumour cell sensitisation to improve therapeutic outcomes of photodynamic (PDT), photothermal (PTT) and radiation (RT), targeted and chemotherapies. Nanoceria has been engineered as a nanocarrier to improve drug delivery or in combination with other drugs to produce synergistic anti-cancer effects. Despite reported preclinical successes, there are still knowledge gaps arising from the inadequate number of studies reporting findings based on physiologically relevant disease models that accurately represent the complexities of cancer. This review discusses the dual-catalytic activities of nanoceria responding to pH and oxygen tension gradient in tumour microenvironment, highlights the recent nanoceria-based platforms reported to be feasible direct and indirect anti-cancer agents with protective effects on healthy tissues, and finally addresses the challenges in clinical translation of nanoceria based therapeutics.
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