HCK Promotes High-Grade Serous Ovarian Cancer Tumorigenesis through CD44 and NOTCH3 Signaling.

High-grade serous ovarian cancer (HGSOC) is a highly aggressive and lethal subtype of ovarian cancer. While most patients initially respond to standard-of-care treatment, the majority will eventually relapse and succumb to their disease. Despite significant advances in our understanding of this disease, the mechanisms that govern the distinctions between HGSOC with good and poor prognosis remain unclear. In this study, we implemented a proteogenomic approach to analyze gene expression, proteomic and phosphoproteomic profiles of HGSOC tumor samples to identify molecular pathways that distinguish HGSOC tumors relative to clinical outcome. Our analyses identify significant upregulation of hematopoietic cell kinase (HCK) expression and signaling in poor prognostic HGSOC patient samples. Analyses of independent gene expression datasets and IHC of patient samples confirmed increased HCK signaling in tumors relative to normal fallopian or ovarian samples and demonstrated aberrant expression in tumor epithelial cells. Consistent with the association between HCK expression and tumor aggressiveness in patient samples, in vitro phenotypic studies showed that HCK can, in part, promote cell proliferation, colony formation, and invasive capacity of cell lines. Mechanistically, HCK mediates these phenotypes, partly through CD44 and NOTCH3-dependent signaling, and inhibiting CD44 or NOTCH3 activity, either genetically or through gamma-secretase inhibitors, can revert HCK-driven phenotypes. IMPLICATIONS: Collectively, these studies establish that HCK acts as an oncogenic driver of HGSOC through aberrant activation of CD44 and NOTCH3 signaling and identifies this network as a potential therapeutic opportunity in a subset of patients with aggressive and recurrent HGSOC.

Central European 2018 hot drought shifts scots pine forest to its tipping point.

The occurrence of hot drought, i.e. low water availability and simultaneous high air temperature, represents a severe threat to ecosystems. Here, we investigated how the 2018 hot drought in Central Europe caused a tipping point in tree and ecosystem functioning in a Scots pine (Pinus sylvestris L.) forest in southwest Germany. Measurements of stress indicators, such as needle water potential, carbon assimilation and volatile organic compound (VOC) emissions, of dominant P. sylvestris trees were deployed to evaluate tree functioning during hot drought. Ecosystem impact and recovery were assessed as ecosystem carbon exchange, normalized difference vegetation index (NDVI) from satellite data and tree mortality data. During summer 2018, needle water potentials of trees dropped to minimum values of -7.5 ± 0.2 MPa, which implied severe hydraulic impairment of P. sylvestris. Likewise, carbon assimilation and VOC emissions strongly declined after mid-July. Decreasing NDVI values from August 2018 onwards were detected, along with severe defoliation in P. sylvestris, impairing ecosystem carbon flux recovery in 2019, shifting the forest into a year-round carbon source. A total of 47% of all monitored trees (n = 368) died by September 2020. NDVI recovered to pre-2018 levels in 2019, likely caused by emerging broadleaved understorey species. The 2018 hot drought had severe negative impacts on P. sylvestris. The co-occurrence of unfavourable site-specific conditions with recurrent severe droughts resulted in accelerated mortality. Thus, the 2018 hot drought pushed the P. sylvestris stand towards its tipping point, with a subsequent vegetation shift to a broadleaf-dominated forest.

Urban Water Storage Capacity Inferred From Observed Evapotranspiration Recession.

Water storage plays an important role in mitigating heat and flooding in urban areas. Assessment of the water storage capacity of cities remains challenging due to the inherent heterogeneity of the urban surface. Traditionally, effective storage has been estimated from runoff. Here, we present a novel approach to estimate effective water storage capacity from recession rates of observed evaporation during precipitation-free periods. We test this approach for cities at neighborhood scale with eddy-covariance based latent heat flux observations from 14 contrasting sites with different local climate zones, vegetation cover and characteristics, and climates. Based on analysis of 583 drydowns, we find storage capacities to vary between 1.3 and 28.4 mm, corresponding to e-folding timescales of 1.8-20.1 days. This makes the urban storage capacity at least five times smaller than all the observed values for natural ecosystems, reflecting an evaporation regime characterized by extreme water limitation.

SOX4 and SMARCA4 cooperatively regulate PI3k signaling through transcriptional activation of TGFBR2.

Dysregulation of PI3K/Akt signaling is a dominant feature in basal-like or triple-negative breast cancers (TNBC). However, the mechanisms regulating this pathway are largely unknown in this subset of aggressive tumors. Here we demonstrate that the transcription factor SOX4 is a key regulator of PI3K signaling in TNBC. Genomic and proteomic analyses coupled with mechanistic studies identified TGFBR2 as a direct transcriptional target of SOX4 and demonstrated that TGFBR2 is required to mediate SOX4-dependent PI3K signaling. We further report that SOX4 and the SWI/SNF ATPase SMARCA4, which are uniformly overexpressed in basal-like tumors, form a previously unreported complex that is required to maintain an open chromatin conformation at the TGFBR2 regulatory regions in order to mediate TGFBR2 expression and PI3K signaling. Collectively, our findings delineate the mechanism by which SOX4 and SMARCA4 cooperatively regulate PI3K/Akt signaling and suggest that this complex may play an essential role in TNBC genesis and/or progression.

Recent Advances in Integrative Multi-Omics Research in Breast and Ovarian Cancer.

The underlying molecular heterogeneity of cancer is responsible for the dynamic clinical landscape of this disease. The combination of genomic and proteomic alterations, including both inherited and acquired mutations, promotes tumor diversity and accounts for variable disease progression, therapeutic response, and clinical outcome. Recent advances in high-throughput proteogenomic profiling of tumor samples have resulted in the identification of novel oncogenic drivers, tumor suppressors, and signaling networks; biomarkers for the prediction of drug sensitivity and disease progression; and have contributed to the development of novel and more effective treatment strategies. In this review, we will focus on the impact of historical and recent advances in single platform and integrative proteogenomic studies in breast and ovarian cancer, which constitute two of the most lethal forms of cancer for women, and discuss the molecular similarities of these diseases, the impact of these findings on our understanding of tumor biology as well as the clinical applicability of these discoveries.

A massively parallel barcoded sequencing pipeline enables generation of the first ORFeome and interactome map for rice.

Systematic mappings of protein interactome networks have provided invaluable functional information for numerous model organisms. Here we develop PCR-mediated Linkage of barcoded Adapters To nucleic acid Elements for sequencing (PLATE-seq) that serves as a general tool to rapidly sequence thousands of DNA elements. We validate its utility by generating the ORFeome for Oryza sativa covering 2,300 genes and constructing a high-quality protein-protein interactome map consisting of 322 interactions between 289 proteins, expanding the known interactions in rice by roughly 50%. Our work paves the way for high-throughput profiling of protein-protein interactions in a wide range of organisms.

Symposium review: Multiple-trait single-step genomic evaluation for hoof health.

Hoof lesions represent an important issue in modern dairy herds, with reported prevalence in different countries ranging from 40 to 70%. This high prevalence of hoof lesions has both economic and social consequences, resulting in increased labor expenses and decreasing animal production, longevity, reproduction, health, and welfare. Therefore, a key goal of dairy herds is to reduce the incidence of hoof lesions, which can be achieved both by improving management practices and through genetic selection. The Canadian dairy industry has recently released a hoof health sub-index. This national genetic evaluation program for hoof health was achieved by creating a centralized data collection system that routinely transfers data recorded by hoof trimmers into a coherent and sustainable national database. The 8 most prevalent lesions (digital dermatitis, interdigital dermatitis, interdigital hyperplasia, heel horn erosion, sole hemorrhage, sole ulcer, toe ulcer, and white line lesion) in Canada are analyzed with a multiple-trait model using a single-step genomic BLUP method. Estimated genomic breeding values for each lesion are combined into a sub-index according to their economic value and prevalence. In addition, data recorded within this system were used to create an interactive management report for dairy producers by Canadian DHI, including the prevalence of lesions on farm, their trends over time, and benchmarks with provincial and national averages.

Integrative proteogenomic analyses of human tumours identifies ADNP as a novel oncogenic mediator of cell cycle progression in high-grade serous ovarian cancer with poor prognosis.

BACKGROUND: Despite toxic side effects and limited durable response, the current standard-of-care treatment for high grade serous ovarian cancer (HGSOC) remains platinum/taxane-based chemotherapy. Given that the overall prognosis has not improved drastically over the past several decades, there is a critical need to understand the underlying mechanisms that lead to tumour development and progression. METHODS: We utilized an integrative proteogenomic analysis of HGSOC tumours applying a poor prognosis gene expression signature (PPS) as a conceptual framework to analyse orthogonal genomic and proteomic data from the TCGA (n = 488) and CPTAC (n = 169) studies. Genes identified through in silico analyses were assessed in vitro studies to demonstrate their impact on proliferation and cell cycle progression. FINDINGS: These analyses identified DNA amplification and overexpression of the transcription factor ADNP (Activity Dependent Neuroprotector Homeobox) in poorly prognostic tumours. Validation studies confirmed the prognostic capacity of ADNP and suggested an oncogenic role for this protein given the association between ADNP expression and pro-proliferative signalling. In vitro studies confirmed ADNP as a novel and essential mediator of cell proliferation through dysregulation of cell cycle checkpoints. INTERPRETATION: We identified ADNP as being amplified and overexpressed in poor prognosis HGSOC in silico analyses and demonstrated that ADNP is a novel and essential oncogene in HGSOC which mediates proliferation through dysregulation of cell cycle checkpoints in vitro. FUNDING: The National Cancer Institute of the National Institutes of Health, the V Foundation for Cancer Research and the New Jersey Commission for Cancer Research.

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.

Each human genome carries tens of thousands of coding variants. The extent to which this variation is functional and the mechanisms by which they exert their influence remains largely unexplored. To address this gap, we leverage the ExAC database of 60,706 human exomes to investigate experimentally the impact of 2009 missense single nucleotide variants (SNVs) across 2185 protein-protein interactions, generating interaction profiles for 4797 SNV-interaction pairs, of which 421 SNVs segregate at > 1% allele frequency in human populations. We find that interaction-disruptive SNVs are prevalent at both rare and common allele frequencies. Furthermore, these results suggest that 10.5% of missense variants carried per individual are disruptive, a higher proportion than previously reported; this indicates that each individual's genetic makeup may be significantly more complex than expected. Finally, we demonstrate that candidate disease-associated mutations can be identified through shared interaction perturbations between variants of interest and known disease mutations.

Repeat gamma knife stereotactic radiosurgery in the treatment of trigeminal neuralgia: A single-center experience and focused review of the literature.

OBJECTIVES: Repeat Gamma Knife stereotactic radiosurgery (GKSR) for refractory trigeminal neuralgia (TGN) is an increasingly common practice. Prior studies have reported varying success rates and incidence of trigeminal nerve dysfunction following repeated GKSR. We report treatment outcomes and toxicity in patients following repeat GKSR for TGN at the University of Alabama at Birmingham (UAB) with a focused review of the literature. METHODS: We retrospectively reviewed medical records of 55 TGN patients re-treated with radiosurgery using the Leksell Gamma Knife® at the University of Alabama at Birmingham between 1996 and 2012. Outcomes were defined using the Modified Marseille Scale. Demographics, prior treatments and symptom duration were correlated with outcomes. RESULTS: Eighteen patients (33%) achieved Marseille Class I or II, 14 (25%) Class III or IV, and 23 (42%) Class V at a mean follow-up of 14.4 months. Twenty-five patients (45%) developed new trigeminal nerve dysfunction after re-treatment. Of these, four (16%) did not develop dysfunction until subsequent microvascular decompression (MVD) for inadequate symptom relief. CONCLUSIONS: Although more than half of the patients undergoing repeat GKSR for refractory TGN maintained excellent or good outcomes (Marseille classes I-IV) at an average follow-up of 14.4 months, neither age, gender, nor pre-treatment duration of symptoms or interval between treatments had a statistically significant effect on outcomes. Following repeat GKSR, patients have increased risk for new-onset trigeminal nerve dysfunction and those undergoing MVD after repeat GKSR may have an increased risk for new-onset trigeminal nerve dysfunction.

Large-scale determination of micropollutant elimination from municipal wastewater by passive sampling gives new insights in governing parameters and degradation patterns.

A simple balancing method using passive samplers over a week's period has been developed and tested successfully to determine elimination rates of 22 common micropollutants of household and industrial sources in 18 full-scale wastewater treatment plants of different design and performance. Independent reactor tests to delineate elimination rates with native sludge of the treatment plants correlated very well with the full-scale elimination rate determinations. As opposed to common assumptions, this large dataset indicated that shorter sludge retention times - read: higher active biomass - showed higher micropollutant elimination rates in many cases. Multivariate statistical analysis of the elimination rates over the 18 treatment plants was able to group compounds according to common degradation pathways and showed that sensitivity to SRT drove the grouping. The dataset also allowed to determine population equivalent normalized loads of the investigated micropollutants. The application of WWTP balancing with passive sampling makes it relatively easy to gather elimination rates and inlet loads on a much broader basis than before and gives orientation for more in-depth analysis of degradation pathways.

Parkin targets HIF-1α for ubiquitination and degradation to inhibit breast tumor progression.

Mutations in E3 ubiquitin ligase Parkin have been linked to familial Parkinson's disease. Accumulating evidence suggests that Parkin is a tumor suppressor, but the underlying mechanism is poorly understood. Here we show that Parkin is an E3 ubiquitin ligase for hypoxia-inducible factor 1α (HIF-1α). Parkin interacts with HIF-1α and promotes HIF-1α degradation through ubiquitination, which in turn inhibits metastasis of breast cancer cells. Parkin downregulation in breast cancer cells promotes metastasis, which can be inhibited by targeting HIF-1α with RNA interference or the small-molecule inhibitor YC-1. We further identify lysine 477 (K477) of HIF-1α as a major ubiquitination site for Parkin. K477R HIF-1α mutation and specific cancer-associated Parkin mutations largely abolish the functions of Parkin to ubiquitinate HIF-1α and inhibit cancer metastasis. Importantly, Parkin expression is inversely correlated with HIF-1α expression and metastasis in breast cancer. Our results reveal an important mechanism for Parkin in tumor suppression and HIF-1α regulation.

Remote sensing of seasonal light use efficiency in temperate bog ecosystems.

Despite storing approximately half of the atmosphere's carbon, estimates of fluxes between wetlands and atmosphere under current and future climates are associated with large uncertainties, and it remains a challenge to determine human impacts on the net greenhouse gas balance of wetlands at the global scale. In this study we demonstrate that the relationship between photochemical reflectance index, derived from high spectral and temporal multi-angular observations, and vegetation light use efficiency was strong (r2 = 0.64 and 0.58 at the hotspot and darkspot, respectively), and can be utilized to estimate carbon fluxes from remote at temperate bog ecosystems. These results improve our understanding of the interactions between vegetation physiology and spectral characteristics to understand seasonal magnitudes and variations in light use efficiency, opening new perspectives on the potential of this technique over extensive areas with different landcover.

Warming effects on the urban hydrology in cold climate regions.

While approximately 338 million people in the Northern hemisphere live in regions that are regularly snow covered in winter, there is little hydro-climatologic knowledge in the cities impacted by snow. Using observations and modelling we have evaluated the energy and water exchanges of four cities that are exposed to wintertime snow. We show that the presence of snow critically changes the impact that city design has on the local-scale hydrology and climate. After snow melt, the cities return to being strongly controlled by the proportion of built and vegetated surfaces. However in winter, the presence of snow masks the influence of the built and vegetated fractions. We show how inter-year variability of wintertime temperature can modify this effect of snow. With increasing temperatures, these cities could be pushed towards very different partitioning between runoff and evapotranspiration. We derive the dependency of wintertime runoff on this warming effect in combination with the effect of urban densification.

Genetic parameters for hoof health traits estimated with linear and threshold models using alternative cohorts.

A national genetic evaluation program for hoof health could be achieved by using hoof lesion data collected directly by hoof trimmers. However, not all cows in the herds during the trimming period are always presented to the hoof trimmer. This preselection process may not be completely random, leading to erroneous estimations of the prevalence of hoof lesions in the herd and inaccuracies in the genetic evaluation. The main objective of this study was to estimate genetic parameters for individual hoof lesions in Canadian Holsteins by using an alternative cohort to consider all cows in the herd during the period of the hoof trimming sessions, including those that were not examined by the trimmer over the entire lactation. A second objective was to compare the estimated heritabilities and breeding values for resistance to hoof lesions obtained with threshold and linear models. Data were recorded by 23 hoof trimmers serving 521 herds located in Alberta, British Columbia, and Ontario. A total of 73,559 hoof-trimming records from 53,654 cows were collected between 2009 and 2012. Hoof lesions included in the analysis were digital dermatitis, interdigital dermatitis, interdigital hyperplasia, sole hemorrhage, sole ulcer, toe ulcer, and white line disease. All variables were analyzed as binary traits, as the presence or the absence of the lesions, using a threshold and a linear animal model. Two different cohorts were created: Cohort 1, which included only cows presented to hoof trimmers, and Cohort 2, which included all cows present in the herd at the time of hoof trimmer visit. Using a threshold model, heritabilities on the observed scale ranged from 0.01 to 0.08 for Cohort 1 and from 0.01 to 0.06 for Cohort 2. Heritabilities estimated with the linear model ranged from 0.01 to 0.07 for Cohort 1 and from 0.01 to 0.05 for Cohort 2. Despite a low heritability, the distribution of the sire breeding values showed large and exploitable variation among sires. Higher breeding values for hoof lesion resistance corresponded to sires with a higher prevalence of healthy daughters. The rank correlations between estimated breeding values ranged from 0.96 to 0.99 when predicted using either one of the 2 cohorts and from 0.94 to 0.99 when predicted using either a threshold or a linear model.

Spatial Characteristics of Roughness Sublayer Mean Flow and Turbulence Over a Realistic Urban Surface.

Single-point measurements from towers in cities cannot properly quantify the impact of all terms in the turbulent kinetic energy (TKE) budget and are often not representative of horizontally-averaged quantities over the entire urban domain. A series of large-eddy simulations (LES) is here performed to quantify the relevance of non-measurable terms, and to explore the spatial variability of the flow field over and within an urban geometry in the city of Basel, Switzerland. The domain has been chosen to be centered around a tower where single-point turbulence measurements at six heights are available. Buildings are represented through a discrete-forcing immersed boundary method and are based on detailed real geometries from a surveying dataset. The local model results at the tower location compare well against measurements under near-neutral stability conditions and for the two prevailing wind directions chosen for the analysis. This confirms that LES in conjunction with the immersed boundary condition is a valuable model to study turbulence and dispersion within a real urban roughness sublayer (RSL). The simulations confirm that mean velocity profiles in the RSL are characterized by an inflection point z γ located above the average building height z h . TKE in the RSL is primarily produced above z γ , and turbulence is transported down into the urban canopy layer. Pressure transport is found to be significant in the very-near-wall regions. Further, spatial variations of time-averaged variables and non-measurable dispersive terms are important in the RSL above a real urban surface and should therefore be considered in future urban canopy parametrization developments.

Review of intellectual assessment measures for children who are deaf or hard of hearing.

OVERVIEW: Intellectual assessment of children who are deaf or hard of hearing presents unique challenges to the clinician charged with attempting to obtain an accurate representation of the child's skills. Selection of appropriate intellectual assessment instruments requires a working knowledge of the strengths and weaknesses of the measure and what changes in standardized administration might be necessary to accommodate for the needs of children who are deaf or hard of hearing. In the case of some available instruments, there is limited guidance and objective research available examining the performance of children who are deaf or hard of hearing. This review summarizes available information on widely used and most recent editions of intellectual assessment measures with special attention to guidance on accommodations, score interpretation, subtest selection and other test-specific considerations when assessing children who are deaf or hard of hearing. SUMMARY: There is much opportunity for further inquiry in the field of intellectual assessment as it applies to children who are deaf or hard of hearing, as many measures have not been closely scrutinized for their appropriate use with this population. Clinicians must recognize inherent difficulties with intellectual assessment measures with children who are deaf or hard of hearing and issues in providing for an accessible and accurate administration of test items.

Deaf children with autism spectrum disorders.

Epidemiological studies investigating the prevalence of autism have increased in recent years, within the United States and abroad. However, statistics as to how many of those children may also have a comorbid hearing loss is lacking. The prevalence of school-administrator reported diagnosis of autism spectrum disorders (clinical diagnosis [DSM-IV] and/or IDEA classification) among children with hearing loss in the US was estimated from the 2009­2010 Annual Survey of Deaf and Hard of Hearing Children and Youth conducted by the Gallaudet Research Institute. Results indicate that during the 2009­2010 school year 1 in 59 children (specifically 8-year olds) with hearing loss were also receiving services for autism; considerably higher, than reported national estimates of 1 in 91 (Koganet al. in Pediatrics 124(4):1­8, 2009) and 1 in 110 (CDC 2007) for hearing children. Significantly more children with profound hearing loss had a comorbid diagnosis of autism than those with milder forms of hearing loss. These results are discussed, while highlighting the need for increased awareness and research in a population that has thus far received little services or attention.

Long-term changes and variability in diabetes risk factors prior to the development of impaired glucose homeostasis.

AIMS: To determine whether rate of change and variability in risk factors provides insight into the development of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or Type 2 diabetes (DM). METHODS: In a nested case-control study, repeated risk factor measurements (mean number 4.3, duration 11.4 years) culminated in 59 men developing IFG (n = 37), IGT (n = 14) and/or DM (n = 11). For each case, two control subjects were matched for age and equivalence of follow-up. Rates of change and variability in diabetes risk factors prior to diagnosis were quantified by regression analysis. Changes between penultimate and diagnostic visits were also analysed. RESULTS: The age-related rise in body mass index (BMI) was attenuated prior to IFG compared with control subjects (+0.102 vs. +0.772 kg/m2/decade, P = 0.02). There was also some evidence for this prior to IGT and DM (IGT: -1.530 vs. +0.158 kg/m2/decade, P = 0.09; DM: -1.146 vs. +0.332 kg/m2/decade, non-significant). Prior to onset, IGT cases were distinguished by higher inflammatory marker levels, a decline in insulinogenic index and greater variability in oral glucose tolerance test (OGTT) insulin, and DM cases by lower insulin sensitivity and higher liver enzyme activities. Fasting and OGTT glucose levels changed little during the mean 8.9 years prior to onset of IFG, IGT or DM. The transition to IGT or DM was accompanied by a fall in insulin sensitivity. CONCLUSIONS: Except for BMI, change or variability in risk factor levels appears relatively unimportant in the development of clinically elevated glucose levels. Deterioration in glucose levels to IGT or DM occurs as a rapid, incremental increase accompanied by a decline in insulin sensitivity.

Intestinal-specific PPARgamma deficiency enhances tumorigenesis in ApcMin/+ mice.

Multiple investigations of the effects of peroxisome proliferator-activated receptor gamma (PPARgamma) ligands on colon cancer have produced contradictory results. While some studies demonstrated increased numbers of colonic polyps in Apc(Min/+) mice treated with various thiazolidinedione (TZD) PPARgamma ligands, others reported amelioration of tumor multiplicity and progression in both Apc(Min/+) mice and in mice with chemically-induced colon cancer. Here, we addressed the role of PPARgamma in murine intestinal tumorigenesis using gene knockout methodology. We found that either heterozygous or homozygous intestinal-specific PPARgamma deficiency enhanced the number of Apc(Min/+) tumors in both the small intestine and colon, especially in the colon, where PPARgamma deficiency also modulated tumor incidence. Gender significantly affected tumor multiplicity independent of PPARgamma genotype. Female Apc(Min/+) mice developed more tumors in the small intestine and more tumors overall, whereas male Apc(Min/+) mice developed more tumors in the colon. Nevertheless, intestinal PPARgamma deficiency enhanced tumorigenesis irrespective of gender. Our results suggest that PPARgamma functions as a tumor resistance factor in the mouse intestine and warrant further investigation of the PPARgamma-dependent and independent actions of TZDs in cancer.