Correlation and colocalization of HIF-1a and pimonidazole staining for hypoxia in laryngeal squamous cell carcinomas:A digital, single-cell-based analysis

OBJECTIVE: Tumor hypoxia results in worse local control and patient survival. We performed a digital, single-cell-based analysis to compare two biomarkers for hypoxia (hypoxia-inducible factor 1-alpha [HIF-1α] and pimonidazole [PIMO]) and their effect on outcome in laryngeal cancer patients treated with accelerated radiotherapy with or without carbogen breathing and nicotinamide (AR versus ARCON). MATERIALS AND METHODS: Immunohistochemical staining was performed for HIF-1α and PIMO in consecutive sections of 44 laryngeal cancer patients randomized between AR and ARCON. HIF-1α expression and PIMO-binding were correlated using digital image analysis in QuPath. High-density areas for each biomarker were automatically annotated and staining overlap was analyzed. Kaplan-Meier survival analyses for local control, regional control and disease-free survival were performed to predict a response benefit of ARCON over AR alone for each biomarker. RESULTS: 106 Tissue fragments of 44 patients were analyzed. A weak, significant positive correlation was observed between HIF-1α and PIMO positivity on fragment level, but not on patient level. A moderate strength correlation (r = 0.705, p < 0.001) was observed between the number of high-density staining areas for both biomarkers. Staining overlap was poor. HIF-1α expression, PIMO-binding or a combination could not predict a response benefit of ARCON over AR. CONCLUSION: Digital image analysis to compare positive cell fractions and staining overlap between two hypoxia biomarkers using open-source software is feasible. Our results highlight that there are distinct differences between HIF-1α and PIMO as hypoxia biomarkers and therefore suggest co-existence of different forms of hypoxia within a single tumor

Association of histological features with laryngeal squamous cell carcinoma recurrences:a population-based study of 1502 patients in the Netherlands

BACKGROUND: Recurrences remain an important problem in laryngeal squamous cell carcinoma. Little has been described about histological characteristics of the primary laryngeal tumor that may be associated with recurrences. Identifying risk factors for recurrences might help in adapting treatment or follow-up. Using real-life population-based data, we aimed to identify histological features of the primary tumor associated with recurrences and overall survival. MATERIAL AND METHODS: Demographic, clinical and treatment information on all first primary invasive laryngeal tumors diagnosed in 2010–2014 (N = 3705) were extracted from the population-based nationwide Netherlands cancer registry (NCR) and linked to PALGA, the nationwide Dutch pathology registry, to obtain data on histological factors and recurrences. For a random 1502 patients histological information i.e., keratinization, perineural invasion (PNI+), vascular invasion (VI+), growth pattern, degree of differentiation, extracapsular spread (ECS+), cartilage- and bone invasion and extralaryngeal extension, was manually extracted from narrative pathology reports and analyzed for locoregional recurrence and overall survival using cox regression analysis. RESULTS: In total, 299 patients developed a locoregional recurrence and 555 patients died. Keratinization (HR = 0.96 (95%CI: 0.68–1.34) p = 0.79), two or three adverse characteristics (PNI+, VI+, non-cohesive growth) (HR = 1.38 (95% CI: 0.63–3.01) p = 0.42), and ECS+ (HR = 1.38 (95% CI: 0.48–4.02) p = 0.55) were not associated to recurrence. For death, also no significant association was found. CONCLUSION: In this population-based real-life dataset on laryngeal carcinoma in the Netherlands, histological factors were not associated with locoregional recurrences or overall survival, but future studies should investigate the role of these features in treatment decisions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-022-09533-0

The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Diabetes mellitus: pathophysiological changes and therap

Predator-specific landscapes of fear and resource distribution: effects on spatial range use.

Although ecologists have long recognized that animal space use is primarily determined by the presence of predators and the distribution of resources, the effects of these two environmental conditions have never been quantified simultaneously in a single spatial model. Here, in a novel approach, predator-specific landscapes of fear are constructed on the basis of behavioral responses of a prey species (vervet monkey; Cercopithecus aethiops), and we show how these can be combined with data on resource distribution to account for the observed variation in intensity of space use. Results from a mixed regressive–spatial regressive analysis demonstrate that ranging behavior can indeed be largely interpreted as an adaptive response to perceived risk of predation by some (but not all) predators and the spatial availability of resources. The theoretical framework behind the model is furthermore such that it can easily be extended to incorporate the effects of additional factors potentially shaping animal range use and thus may be of great value to the study of animal spatial ecology

Mitochondrial Morphofunction in Mammalian Cells

Contains fulltext : 204156.pdf (publisher's version ) (Open Access)Significance: In addition to their classical role in cellular ATP production, mitochondria are of key relevance in various (patho)physiological mechanisms including second messenger signaling, neuro-transduction, immune responses and death induction. Recent Advances: Within cells, mitochondria are motile and display temporal changes in internal and external structure ("mitochondrial dynamics"). During the last decade, substantial empirical and in silico evidence was presented demonstrating that mitochondrial dynamics impacts on mitochondrial function and vice versa. Critical Issues: However, a comprehensive and quantitative understanding of the bidirectional links between mitochondrial external shape, internal structure and function ("morphofunction") is still lacking. The latter particularly hampers our understanding of the functional properties and behavior of individual mitochondrial within single living cells. Future Directions: In this review we discuss the concept of mitochondrial morphofunction in mammalian cells, primarily using experimental evidence obtained within the last decade. The topic is introduced by briefly presenting the central role of mitochondria in cell physiology and the importance of the mitochondrial electron transport chain (ETC) therein. Next, we summarize in detail how mitochondrial (ultra)structure is controlled and discuss empirical evidence regarding the equivalence of mitochondrial (ultra)structure and function. Finally, we provide a brief summary of how mitochondrial morphofunction can be quantified at the level of single cells and mitochondria, how mitochondrial ultrastructure/volume impacts on mitochondrial bioreactions and intramitochondrial protein diffusion, and how mitochondrial morphofunction can be targeted by small molecules

Remotely sensed productivity, home range selection and local range use by an omnivorous primate

Remote sensing of the environment has proved an invaluable tool to the study of animal ecology at continental to regional scales. Here, we investigated the utility of a remotely sensed index of plant productivity (the normalized difference vegetation index [NDVI]) at a much finer spatial scale to account for the range use of an omnivorous primate (the vervet monkey: Cercopithecus aethiops) foraging in a multipredator environment. Vervet monkey home range location suggested that the animals prefer areas with elevated productivity and reduced seasonality as indexed by simple NDVI metrics. Within the annual home range area, monthly NDVI values were linearly related to field measurements of leaf cover and quadratically associated with vervet monkey food availability. Temporal variation in parameters of local range use could subsequently be expressed in terms of local NDVI: Monthly averaged day journey length showed a second-order polynomial response, and the amount of time the monkeys spent on the ground increased with group size whereas linearly decreasing with monthly NDVI. The first finding signifies a behavioral response to food availability, whereas the latter is interpreted as an antipredatory response to changes in habitat visibility, associated with leaf cover. As a spatially explicit and temporally varying measure of habitat structure and productivity, the NDVI thus offers considerable scope for studies of animal behavioral ecology not only at broad spatiotemporal scales but also at a much finer grained level of analysis

Taxonomy and distribution of bottlenose dolphins in Australian waters: an osteological clarification.

Species relationships in the genus Tursiops are controversial. We carried out a comprehensive osteological study of 264 skulls, including type specimens, and 90 postcranial skeletons of Tursiops spp., to address taxonomic uncertainties in Australia using two-dimensional measurements (2D), and three-dimensional geometric morphometrics (3DGM), tooth counts, and categorical data. Analyses provided support for the presence of two forms, aligned to T. aduncus (Ehrenberg, 1832) and T. truncatus (Montagu, 1821), including type specimens. Tursiops australis (Charlton-Robb et al. 2011) fell well within T. truncatus for both methods. Thirteen Tursiops spp. specimens, no T. australis specimens, were of intermediate size (2D) and could not be assigned to either species. For 3DGM data there was a strong allometric influence and few non-allometric differences between species. Length and width of the cranium and rostrum were important discriminating variables. Tursiops aduncus was smaller, had more teeth, fewer vertebrae, and more erosion on the pterygoids and frontals than T. truncatus. Overall cranium shape was round in T. aduncus and angular in T. truncatus. Skull length of T. aduncus was smaller in low than in high latitudes. This study highlights the importance of large sample size, multiple analytical methods and extensive geographical coverage when undertaking taxonomic studies

Demography and life history of Thomas Langurs (Presbytis thomasi)

Life history data from wild primate populations are necessary to explain variation in primate social systems and explain differences between primates and other mammals. Here we report life history data from a 12.5-year study on wild Thomas langurs. Mean age at first reproduction was 5.4 years and the sex ratio at birth was even. The mean interbirth interval (IBI) after a surviving infant was 26.8 mo, after nonsurviving infants 17.7 mo, and combined 22.0 mo. Mean annual birth rate of adult females was 0.44, while reaching a peak at 6 years of age and showing no decrease with age. Mortality was highest during the first year of life (48.0% for males and 43.0% for females) and consistently higher for males than females. The oldest female observed during the study was estimated to be 20 years of age, whereas the oldest male disappeared at age 13 years, indicating that males die at a much earlier age than females. A Leslie matrix based on these estimates yielded a growth rate of 1.01, which is comparable to the nonsignificant increase in density indicated by our long-term field data. A comparison with life history data for sympatric frugivorous primates suggests that folivory might be associated with faster life history. © 2006 Wiley-Liss, Inc