Shrub expansion in tundra ecosystems: dynamics, impacts and research priorities

Part of Focus on Dynamics of Arctic and Sub-Arctic Vegetation Recent research using repeat photography, long-term ecological monitoring and dendrochronology has documented shrub expansion in arctic, high-latitude and alpine tundra ecosystems. Here, we (1) synthesize these findings, (2) present a conceptual framework that identifies mechanisms and constraints on shrub increase, (3) explore causes, feedbacks and implications of the increased shrub cover in tundra ecosystems, and (4) address potential lines of investigation for future research. Satellite observations from around the circumpolar Arctic, showing increased productivity, measured as changes in 'greenness', have coincided with a general rise in high-latitude air temperatures and have been partly attributed to increases in shrub cover. Studies indicate that warming temperatures, changes in snow cover, altered disturbance regimes as a result of permafrost thaw, tundra fires, and anthropogenic activities or changes in herbivory intensity are all contributing to observed changes in shrub abundance. A large-scale increase in shrub cover will change the structure of tundra ecosystems and alter energy fluxes, regional climate, soil–atmosphere exchange of water, carbon and nutrients, and ecological interactions between species. In order to project future rates of shrub expansion and understand the feedbacks to ecosystem and climate processes, future research should investigate the species or trait-specific responses of shrubs to climate change including: (1) the temperature sensitivity of shrub growth, (2) factors controlling the recruitment of new individuals, and (3) the relative influence of the positive and negative feedbacks involved in shrub expansion

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Risk Prediction Scores for Recurrence and Progression of Non-Muscle Invasive Bladder Cancer: An International Validation in Primary Tumours

Abstract Objective: We aimed to determine the validity of two risk scores for patients with non-muscle invasive bladder cancer in different European settings, in patients with primary tumours. Methods: We included 1,892 patients with primary stage Ta or T1 non-muscle invasive bladder cancer who underwent a transurethral resection in Spain (n = 973), the Netherlands (n = 639), or Denmark (n = 280). We evaluated recurrence-free survival and progression-free survival according to the European Organisation for Research and Treatment of Cancer (EORTC) and the Spanish Urological Club for Oncological Treatment (CUETO) risk scores for each patient and used the concordance index (c-index) to indicate discriminative ability. Results: The 3 cohorts were comparable according to age and sex, but patients from Denmark had a larger proportion of patients with the high stage and grade at diagnosis (p,0.01). At least one recurrence occurred in 839 (44%) patients and 258 (14%) patients had a progression during a median follow-up of 74 months. Patients from Denmark had the highest 10- year recurrence and progression rates (75% and 24%, respectively), whereas patients from Spain had the lowest rates (34% and 10%, respectively). The EORTC and CUETO risk scores both predicted progression better than recurrence with c-indices ranging from 0.72 to 0.82 while for recurrence, those ranged from 0.55 to 0.61. Conclusion: The EORTC and CUETO risk scores can reasonably predict progression, while prediction of recurrence is more difficult. New prognostic markers are needed to better predict recurrence of tumours in primary non-muscle invasive bladder cancer patients.This research received funding from the European Community's Seventh Framework program FP7/2007-2011 under grant agreement 201663 (Uromol project, http://www.uromol.eu/

Update for the practicing pathologist: The International Consultation On Urologic Disease-European association of urology consultation on bladder cancer

The International Consultations on Urological Diseases are international consensus meetings, supported by the World Health Organization and the Union Internationale Contre le Cancer, which have occurred since 1981. Each consultation has the goal of convening experts to review data and provide evidence-based recommendations to improve practice. In 2012, the selected subject was bladder cancer, a disease which remains a major public health problem with little improvement in many years. The proceedings of the 2nd International Consultation on Bladder Cancer, which included a 'Pathology of Bladder Cancer Work Group,' have recently been published; herein, we provide a summary of developments and consensus relevant to the practicing pathologist. Although the published proceedings have tackled a comprehensive set of issues regarding the pathology of bladder cancer, this update summarizes the recommendations regarding selected issues for the practicing pathologist. These include guidelines for classification and grading of urothelial neoplasia, with particular emphasis on the approach to inverted lesions, the handling of incipient papillary lesions frequently seen during surveillance of bladder cancer patients, descriptions of newer variants, and terminology for urine cytology reporting

Centrosome clustering and Cyclin D1 gene amplification in double minutes are common events in chromosomal unstable bladder tumors

Background: Aneuploidy, centrosome abnormalities and gene amplification are hallmarks of chromosome instability (CIN) in cancer. Yet there are no studies of the in vivo behavior of these phenomena within the same bladder tumor. Methods: Twenty-one paraffin-embedded bladder tumors were analyzed by conventional comparative genome hybridization and fluorescence in situ hybridization (FISH) with a cyclin D1 gene (CCND1)/centromere 11 dual-color probe. Immunofluorescent staining of α, β and γ tubulin was also performed. Results: Based on the CIN index, defined as the percentage of cells not displaying the modal number for chromosome 11, tumors were classified as CIN-negative and CIN-positive. Fourteen out of 21 tumors were considered CIN-positive. All T1G3 tumors were included in the CIN-positive group whereas the majority of Ta samples were classified as CIN-negative tumors. Centrosome clustering was observed in six out of 12 CIN-positive tumors analyzed. CCND1 amplification in homogeneously staining regions was present in six out of 14 CIN-positive tumors; three of them also showed amplification of this gene in double minutes. Conclusions: Complex in vivo behavior of CCND1 amplicon in bladder tumor cells has been demonstrated by accurate FISH analysis on paraffin-embedded tumors. Positive correlation between high heterogeneity, centrosome abnormalities and CCND1 amplification was found in T1G3 bladder carcinomas. This is the first study to provide insights into the coexistence of CCND1 amplification in homogeneously staining regions and double minutes in primary bladder tumors. It is noteworthy that those patients whose tumors showed double minutes had a significantly shorter overall survival rate (p < 0.001)

Повторные измерения толщины слоя нервных волокон с помощью оптического когерентного томографа Stratus

PURPOSE: Assessment of optic disc damage is an essential part of the ocular examination and differential diagnosis between the patient with ocular hypertension and pre-perimetric or perimetric glaucoma. The Stratus optic coherent tomograph (Carl Zeiss Meditec, Inc, Dublin, Calif) is still one of the most used optic nerve imaging technology throughout the world. Therefore, the development of methodology that enhances the utility of optic disc measurements with the Stratus OCT remains a relevant and meaningful goal. In an attempt to determine the optimal number of repeated measurements we investigated how the average of three sets of manually repeated measurements of retina nerve firer layer (RNFL) thickness would compare with a single set. METHODS: A total of 73 individuals (136 eyes) aged 55.3±15.2 years with ocular hypertensive (OHT), pre-peri-metric glaucoma or glaucoma were included in the final analysis. When the data was evaluated using a quadrant analysis we observed that 13.6% of the patients exhibited a clinically meaningful difference of 20% or more in the serial RNFL thickness measurements. RESULTS: The difference ranged from 9.3 to 32.7 microns and in 10 of the 12 quadrants the averaged measurement exceeded the initial measurement. Most of the differences demonstrated in this study occurred in the horizontal meridian and are probably a result of instinctive saccadic eye movements. A difference in the vertical meridian (superior and/or inferior quadrants) which is the more relevant meridian for changes in glaucoma was seen in only 3 patients (4.1%). CONCLUSIONS: One reliable RNFL measurement would be sufficient in most of these cases because in 95.9% of the cases the differences observed for the vertical meridian were less than 20%. Nevertheless, it is important to recognize that there can be more variability in the horizontal meridian and that in cases with visual loss encroaching on fixation serial measurements may be useful. At any rate, as with all ancillary tests, whenever a change is detected, it is wise to repeat the test to verify the results.ЦЕЛЬ. Оценка изменений в диске зрительного нерва является важной частью офтальмологического обследования и дифференциальной диагностики у пациентов с офтальмогипертензией и ранней и развитой стадиями глаукомы. Оптический когерентный томограф Stratus (Carl Zeiss Meditec, Inc, Dublin, Calif) до сих пор является одним из самых часто используемых приборов для визуализации зрительного нерва по всему миру. Поэтому разработка методологии, оптимизирующей оценку состояния диска зрительного нерва с помощью Stratus, остается важной и актуальной задачей. В попытке определить оптимальное количество последовательных измерений, мы сравнивали результаты одиночного измерения толщины слоя нервных волокон с усредненными результатами серии из трех последовательных измерений. методы. Всего в исследовании участвовало 73 пациента (136 глаз) в возрасте 55,3±15,2 года с офтальмогипертензией или диагностированной глаукомой. При анализе полученных данных по квадрантам поля зрения у 13,6% пациентов было обнаружено клинически значимое различие ≥ 20% в толщине слоя нервных волокон. РЕЗУЛЬТАТЫ. Разница в измерениях составляла от 9,3 до 32,7 мкм, и в 10 из 12 квадрантов усредненный результат трех последовательных измерений превышал результат единичного измерения. В большинстве случав различие отмечалось в горизонтальном меридиане и, вероятно, являлось результатом естественных саккадных движений. Различие в результатах по более значимому для изменений поля зрения при глаукоме вертикальному меридиану (верхние и/или нижние квадранты) наблюдалось только у 3 (4,1%) пациентов. ЗАКЛЮЧЕНИЕ. Поскольку в 95,9% случаев разница результатов по вертикальному меридиану не превышает 20%, можно сделать вывод, что в большинстве случаев достаточно одного достоверного измерения толщины слоя нервных волокон сетчатки. Тем не менее полезно помнить о большей вариабельности результатов по горизонтальному меридиану. Например, в случае со снижением зрения, затрудняющим фиксацию взгляда, может быть полезным проведение серии из нескольких исследований подряд. В любом случае при появлении изменений в результатах этого или других вспомогательных исследований наилучшей тактикой является повторение исследования для подтверждения результатов

Nested inversion polymorphisms predispose chromosome 22q11.2 to meiotic rearrangements [RETRACTED]

Inversion polymorphisms between low-copy repeats (LCRs) might predispose chromosomes to meiotic non-allelic homologous recombination (NAHR) events and thus lead to genomic disorders. However, for the 22q11.2 deletion syndrome (22q11.2DS), the most common genomic disorder, no such inversions have been uncovered as of yet. Using fiber-FISH, we demonstrate that parents transmitting the de novo 3 Mb LCR22A–D 22q11.2 deletion, the reciprocal duplication, and the smaller 1.5 Mb LCR22A–B 22q11.2 deletion carry inversions of LCR22B–D or LCR22C–D. Hence, the inversions predispose chromosome 22q11.2 to meiotic rearrangements and increase the individual risk for transmitting rearrangements. Interestingly, the inversions are nested or flanking rather than coinciding with the deletion or duplication sizes. This finding raises the possibility that inversions are a prerequisite not only for 22q11.2 rearrangements but also for all NAHR-mediated genomic disorders

Clinicopathological and molecular characterisation of “multiple classifier” endometrial carcinomas

Endometrial carcinoma (EC) molecular classification based on four molecular subclasses identified in The Cancer Genome Atlas (TCGA) has gained relevance in recent years due to its prognostic utility and potential to predict benefit from adjuvant treatment. While most ECs can be classified based on a single classifier (POLE exonuclease domain mutations - POLEmut, MMR deficiency - MMRd, p53 abnormal - p53abn), a small but clinically relevant group of tumours harbour more than one molecular classifying feature and are referred to as 'multiple-classifier' ECs. We aimed to describe the clinicopathological and molecular features of multiple-classifier ECs with abnormal p53 (p53abn). Within a cohort of 3518 molecularly profiled ECs, 107 (3%) tumours displayed p53abn in addition to another classifier(s), including 64 with MMRd (MMRd-p53abn), 31 with POLEmut (POLEmut-p53abn), and 12 with all three aberrations (MMRd-POLEmut-p53abn). MMRd-p53abn ECs and POLEmut-p53abn ECs were mostly grade 3 endometrioid ECs, early stage, and frequently showed morphological features characteristic of MMRd or POLEmut ECs. 18/28 (60%) MMRd-p53abn ECs and 7/15 (46.7%) POLEmut-p53abn ECs showed subclonal p53 overexpression, suggesting that TP53 mutation was a secondary event acquired during tumour progression. Hierarchical clustering of TCGA ECs by single nucleotide variant (SNV) type and somatic copy number alterations (SCNAs) revealed that MMRd-p53abn tumours mostly clustered with single-classifier MMRd tumours (20/23) rather than single-classifier p53abn tumours (3/23), while POLEmut-p53abn tumours mostly clustered with single-classifier POLEmut tumours (12/13) and seldom with single-classifier p53abn tumours (1/13) (both p ≤ 0.001, chi-squared test). Finally, the clinical outcome of patients with MMRd-p53abn and POLEmut-p53abn ECs [stage I 5-year recurrence-free survival (RFS) of 92.2% and 94.1%, respectively] was significantly different from single-classifier p53abn EC (stage I RFS 70.8%, p = 0.024 and p = 0.050, respectively). Our results support the classification of MMRd-p53abn EC as MMRd and POLEmut-p53abn EC as POLEmut. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

Analytical validation of a next generation sequencing liquid biopsy assay for high sensitivity broad molecular profiling.

Circulating tumor DNA (ctDNA) analysis is being incorporated into cancer care; notably in profiling patients to guide treatment decisions. Responses to targeted therapies have been observed in patients with actionable mutations detected in plasma DNA at variant allele fractions (VAFs) below 0.5%. Highly sensitive methods are therefore required for optimal clinical use. To enable objective assessment of assay performance, detailed analytical validation is required. We developed the InVisionFirst™ assay, an assay based on enhanced tagged amplicon sequencing (eTAm-Seq™) technology to profile 36 genes commonly mutated in non-small cell lung cancer (NSCLC) and other cancer types for actionable genomic alterations in cell-free DNA. The assay has been developed to detect point mutations, indels, amplifications and gene fusions that commonly occur in NSCLC. For analytical validation, two 10mL blood tubes were collected from NSCLC patients and healthy volunteer donors. In addition, contrived samples were used to represent a wide spectrum of genetic aberrations and VAFs. Samples were analyzed by multiple operators, at different times and using different reagent Lots. Results were compared with digital PCR (dPCR). The InVisionFirst assay demonstrated an excellent limit of detection, with 99.48% sensitivity for SNVs present at VAF range 0.25%-0.33%, 92.46% sensitivity for indels at 0.25% VAF and a high rate of detection at lower frequencies while retaining high specificity (99.9997% per base). The assay also detected ALK and ROS1 gene fusions, and DNA amplifications in ERBB2, FGFR1, MET and EGFR with high sensitivity and specificity. Comparison between the InVisionFirst assay and dPCR in a series of cancer patients showed high concordance. This analytical validation demonstrated that the InVisionFirst assay is highly sensitive, specific and robust, and meets analytical requirements for clinical applications

'Tough'-constructions and their derivation

This article addresses the syntax of the notorious 'tough' (-movement) construction (TC) in English. TCs exhibit a range of apparently contradictory empirical properties suggesting that their derivation involves the application of both A-movement and A'-movement operations. Given that within previous Principles and Parameters models TCs have remained “unexplained and in principle unexplainable” (Holmberg 2000: 839) due to incompatibility with constraints on theta-assignment, locality, and Case, this article argues that the phase-based implementation of the Minimalist program (Chomsky 2000, 2001, 2004) permits a reanalysis of null wh-operators capable of circumventing the previous theoretical difficulties. Essentially, 'tough'-movement consists of A-moving a constituent out of a “complex” null operator which has already undergone A'-movement, a “smuggling” construction in the terms of Collins (2005a,b