Differences in methylation profiles between HPV-positive and HPV-negative oropharynx squamous cell carcinoma: A systematic review

Oropharyngeal squamous cell carcinoma (OPSCC) is associated with human papillomavirus (HPV). HPV-positive OPSCC is considered a distinct molecular entity with a better prognosis than HPV-negative cases of OPSCC. However, the exact pathogenic mechanisms underlying the differences in clinical and molecular behavior between HPV-positive and HPV-negative OPSCC remain poorly understood. Epigenetic events play an important role in the development of cancer. Hypermethylation of DNA in promoter regions and global hypomethylation are 2 epigenetic changes that have been frequently observed in human cancers. It is suggested that heterogeneous epigenetic changes play a role in the clinical and biological differences between HPV-positive and HPV-negative tumors. Unraveling the differences in methylation profiles of HPV-associated OPSCC may provide for promising clinical applications and may pave the road for personalized cancer treatment. This systematic review aims to assess the current state of knowledge regarding differences in promoter hypermethylation and global methylation between HPV-positive and HPV-negative OPSCC.     

Protective Efficacy of a Single Immunization of a Chimeric Adenovirus Vector-Based Vaccine against Simian Immunodeficiency Virus Challenge in Rhesus Monkeys

Rare serotype and chimeric recombinant adenovirus (rAd) vectors that evade anti-Ad5 immunity are currently being evaluated as potential vaccine vectors for human immunodeficiency virus type 1 and other pathogens. We have recently reported that a heterologous rAd prime-boost regimen expressing simian immunodeficiency virus (SIV) Gag afforded durable partial immune control of an SIV challenge in rhesus monkeys. However, single-shot immunization may ultimately be preferable for global vaccine delivery. We therefore evaluated the immunogenicity and protective efficacy of a single immunization of chimeric rAd5 hexon hypervariable region 48 (rAd5HVR48) vectors expressing SIV Gag, Pol, Nef, and Env against a homologous SIV challenge in rhesus monkeys. Inclusion of Env resulted in improved control of peak and set point SIV RNA levels following challenge. In contrast, DNA vaccine priming did not further improve the protective efficacy of rAd5HVR48 vectors in this system.Heterologous prime-boost vaccine regimens have proven substantially more immunogenic than single vector immunizations in a variety of experimental models, but a single-shot vaccine would presumably be ideal for eventual global delivery. The potential utility of single-shot vaccines against pathogenic simian immunodeficiency virus (SIV) challenges in rhesus monkeys has not been well characterized. We therefore evaluated the protective efficacy of a single immunization of recombinant chimeric adenovirus type 5 (rAd5) hexon hypervariable region 48 (rAd5HVR48) vectors (15) expressing SIV Gag, Pol, Nef, and Env against a pathogenic SIV challenge in rhesus monkeys. These vectors contain the HVRs of the rare Ad48 serotype and have been shown to evade dominant Ad5 hexon-specific neutralizing antibodies (NAbs) (15). We also assessed the potential utility of inclusion of Env as an immunogen (6, 7, 17) and the degree to which DNA vaccine priming would enhance the protective efficacy afforded by a single rAd5HVR48 immunization (2, 7, 18, 21).Thirty adult rhesus monkeys (n = 6/group) lacking the Mamu-A*01, Mamu-B*17, and Mamu-B*08 class I alleles were primed with plasmid DNA vaccines and boosted with rAd5HVR48 vectors as follows: (1) adjuvanted DNA prime, rAd5HVR48 boost; (2) DNA prime, rAd5HVR48 boost; (3) rAd5HVR48 alone; (4) rAd5HVR48 alone (excluding Env); and (5) sham controls. Monkeys in groups 1 to 3 received vectors expressing SIVmac239 Gag, Pol, Nef, and Env, whereas monkeys in group 4 received vectors expressing only Gag, Pol, and Nef. The DNA vaccine adjuvants in group 1 were plasmids expressing the rhesus chemokine MIP-1α and Flt3L, which have been shown to increase recruitment of dendritic cells and to improve DNA vaccine immunogenicity (20). Monkeys were primed intramuscularly with a total dose of 4 mg of DNA vaccines at weeks 0, 4, and 8. All animals then received a single intramuscular immunization of 4 × 10¹⁰ viral particles (vp) of rAd5HVR48 at week 24. At week 52, animals were challenged intravenously (i.v.) with 100 monkey infectious doses of SIVmac251 (7, 10).     

Perceptual compression of space through position integration

The mechanism of positional localization has recently been debated due to interest in the flash-lag effect, which occurs when a briefly flashed stationary stimulus is perceived to lag behind a spatially aligned moving stimulus. Here we report positional localization observed at motion offsets as well as at onsets. In the 'flash-lead' effect, a moving object is perceived to be behind a spatially concurrent stationary flash before the two disappear. With 'reverse-repmo', subjects mis-localize the final position of a moving bar in the direction opposite to the trajectory of motion. Finally, we demonstrate that simultaneous onset and offset effects lead to a perceived compression of visual space. By characterizing illusory effects observed at motion offsets as well as at onsets, we provide evidence that the perceived position of a moving object is the result of an averaging process over a short time period, weighted towards the most recent positions. Our account explains a variety of motion illusions, including the compression of moving shapes when viewed through apertures.     

Targeting selenium metabolism and selenoproteins: novel avenues for drug discovery

Selenoproteins play a wide range of roles in metabolism and oxidative stress defense and are produced by organisms in all three domains of life. Recent evidence has been presented that metal based cancer drugs target the selenol nucleophile of the active site selenocysteine in thioredoxin reductase isoenzymes. Other metals and metalloids, such as tin, arsenic and gold, have also recently been shown to form stable complexes with hydrogen selenide, a required precursor for the synthesis of selenoproteins in all biological organisms. Moreover these metal based compounds have been shown to inhibit growth of pathogens such as Clostridium difficile and Treponema denticola due to their reactivity with this highly reactive metabolic precursor. This review summarizes the recent finding on these two avenues for drug discovery, and puts this work in context with the larger field of selenium biology.     

Temperature change as a driver of spatial patterns and long‐term trends in chironomid (Insecta: Diptera) diversity

Anthropogenic activities have led to a global decline in biodiversity, and monitoring studies indicate that both insect communities and wetland ecosystems are particularly affected. However, there is a need for long‐term data (over centennial or millennial timescales) to better understand natural community dynamics and the processes that govern the observed trends. Chironomids (Insecta: Diptera: Chironomidae) are often the most abundant insects in lake ecosystems, sensitive to environmental change, and, because their larval exoskeleton head capsules preserve well in lake sediments, they provide a unique record of insect community dynamics through time. Here, we provide the results of a metadata analysis of chironomid diversity across a range of spatial and temporal scales. First, we analyse spatial trends in chironomid diversity using Northern Hemispheric data sets overall consisting of 837 lakes. Our results indicate that in most of our data sets, summer temperature (T_jul) is strongly associated with spatial trends in modern‐day chironomid diversity. We observe a strong increase in chironomid alpha diversity with increasing T_jul in regions with present‐day T_jul between 2.5 and 14°C. In some areas with T_jul > 14°C, chironomid diversity stabilizes or declines. Second, we demonstrate that the direction and amplitude of change in alpha diversity in a compilation of subfossil chironomid records spanning the last glacial–interglacial transition (~15,000–11,000 years ago) are similar to those observed in our modern data. A compilation of Holocene records shows that during phases when the amplitude of temperature change was small, site‐specific factors had a greater influence on the chironomid fauna obscuring the chironomid diversity–temperature relationship. Our results imply expected overall chironomid diversity increases in colder regions such as the Arctic under sustained global warming, but with complex and not necessarily predictable responses for individual sites.     

Adenosine‐A3 receptors in neutrophil microdomains promote the formation of bacteria‐tethering cytonemes

The A₃‐adenosine receptor (A₃AR) has recently emerged as a key regulator of neutrophil behaviour. Using a fluorescent A₃AR ligand, we show that A₃ARs aggregate in highly polarized immunomodulatory microdomains on human neutrophil membranes. In addition to regulating chemotaxis, A₃ARs promote the formation of filipodia‐like projections (cytonemes) that can extend up to 100 μm to tether and ‘reel in’ pathogens. Exposure to bacteria or an A₃AR agonist stimulates the formation of these projections and bacterial phagocytosis, whereas an A₃AR‐selective antagonist inhibits cytoneme formation. Our results shed new light on the behaviour of neutrophils and identify the A₃AR as a potential target for modulating their function.     

Analysis of the genomic response of human prostate cancer cells to histone deacetylase inhibitors

Histone deacetylases (HDACs) have emerged as important targets for cancer treatment. HDAC-inhibitors (HDACis) are well tolerated in patients and have been approved for the treatment of patients with cutaneous T-cell lymphoma (CTCL). To improve the clinical benefit of HDACis in solid tumors, combination strategies with HDACis could be employed. In this study, we applied Analysis of Functional Annotation (AFA) to provide a comprehensive list of genes and pathways affected upon HDACi-treatment in prostate cancer cells. This approach provides an unbiased and objective approach to high throughput data mining. By performing AFA on gene expression data from prostate cancer cell lines DU-145 (an HDACi-sensitive cell line) and PC3 (a relatively HDACi-resistant cell line) treated with HDACis valproic acid or vorinostat, we identified biological processes that are affected by HDACis and are therefore potential treatment targets for combination therapy. Our analysis revealed that HDAC-inhibition resulted among others in upregulation of major histocompatibility complex (MHC) genes and deregulation of the mitotic spindle checkpoint by downregulation of genes involved in mitosis. These findings were confirmed by AFA on publicly available data sets from HDACi-treated prostate cancer cells. In total, we analyzed 375 microarrays with HDACi treated and non-treated (control) prostate cancer cells. All results from this extensive analysis are provided as an online research source (available at the journal’s website and at http://luigimarchionni.org/HDACIs.html). By publishing this data, we aim to enhance our understanding of the cellular changes after HDAC-inhibition, and to identify novel potential combination strategies with HDACis for the treatment of prostate cancer patients.     

Distinct Roles of the Cortical Layers of Area V1 in Figure-Ground Segregation

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X-ray structures of checkpoint kinase 2 in complex with inhibitors that target its gatekeeper-dependent hydrophobic pocket

The serine/threonine checkpoint kinase 2 (Chk2) is an attractive molecular target for the development of small molecule inhibitors to treat cancer. Here, we report the rational design of Chk2 inhibitors that target the gatekeeper-dependent hydrophobic pocket located behind the adenine-binding region of the ATP-binding site. These compounds exhibit IC(50) values in the low nanomolar range and are highly selective for Chk2 over Chk1. X-ray crystallography was used to determine the structures of the inhibitors in complex with the catalytic kinase domain of Chk2 to verify their modes of binding.