Glycotope structures and intramolecular affinity factors of plant lectins for Tn/T antigens

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Tumor Heterogeneity of Fibroblast Growth Factor Receptor 3 (FGFR3) Mutations in Invasive Bladder Cancer: Implications for Peri-Operative anti-FGFR3 Treatment

Background: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. Patients: and methods We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201).Results: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type.Conclusions: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting

Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy

© Springer-Verlag GmbH Germany, part of Springer Nature 2018Background: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy. Patients and methods: Patients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes. Results: Of 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the ‘CIS’ versus ‘no-CIS’ groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63–1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01–1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23–2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34–0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82–1.35; p = 0.70). Conclusion: In this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.Peer reviewedFinal Accepted Versio

Combined proteome and transcriptome analyses for the discovery of urinary biomarkers for urothelial carcinoma

Background: Proteomic discovery of cancer biomarkers in body fluids is challenging because of their low abundance in a complex background. Altered gene expression in tumours may not reflect protein levels in body fluids. We have tested combining gene expression profiling of tumours with proteomic analysis of cancer cell line secretomes as a strategy to discover urinary biomarkers for bladder cancer. Methods: We used shotgun proteomics to identify proteins secreted by three bladder cancer cell lines. Secreted proteins with high mRNA levels in bladder tumours relative to normal urothelium were assayed by ELISA in urine samples from 642 patients. Results: Midkine and HAI-1 were significantly increased in bladder cancer patients, with the highest levels in invasive disease (area under the receiver operating characteristic curve 0.89 vs non-cancer). The urinary concentration of both proteins was too high to be explained by bladder cancer associated haematuria and most likely arises by direct tumour secretion. Conclusions: This ‘dual-omic’ strategy identified tumour secreted proteins whose urine concentrations are increased significantly by bladder cancer. Combined secretome-transcriptome analysis may be more useful than direct proteomic analysis of body fluids for biomarker discovery in both bladder cancer and other tumour type

Democracy, protest and public sphere in Russia after the 2011–2012 anti-government protests: digital media at stake

The 2011–2012 Russian protest mobilisations were largely enabled by the rise of social networks. Social and technological advancements paired to pave the way for the ‘biggest protests since the fall of USSR’. Ubiquitous and uncensored social media facilitated the networking and mobilisation for this protest activity: Liberal masses were able to share and discuss their grievances, unite and coordinate online for the offline protest. The digitally savvy protest public developed to confront the government, which appeared to be astonished by the scale of protest. Those mobilisations marked an important gap between the government’s conception of the society and the real state of resistance. This article studies three main hypotheses regarding the potential of the protest movement in Russia. The hypotheses were drawn from recent sociological, political and media studies on Russian resistance. Current research aims to contribute to the debate from the digital media perspective. It therefore evaluates three main assumptions: Digital media have the potential to empower, dependent upon the relevant political, social and economic factors; digital media isolates protest publics and therefore may be more useful for the government than the resistance; and recent censorship of digital media communication signals a tightening of both formal and informal restrictions against opposition and protest politics. This article uses theoretical and factual evidence on the limitations of democracy and the public sphere and conceptualises the government’s management of resistance in Russia during and after the 2011–2012 protests. It studies how the hybrid political regime in Russia balances restrictions on freedom of speech with strengthened state propaganda and how it mediates media oppression and invites self-censorship. Finally, it examines how the state communication watchdog has recently focused its attention at the digital realm. This move confirms the importance of the online protest communication for the Russian political environment. Yet the state’s acknowledgement of digital political resistance may lead to further oppression and curbing of this emerging component of Russian politics

In depth evaluation of the prognostic and predictive utility of PTEN immunohistochemistry in colorectal carcinomas: performance of three antibodies with emphasis on intracellular and intratumoral heterogeneity.

BACKGROUND: Phosphatase and tensin homolog deleted in chromosome 10 (PTEN) loss of function is frequently detected in advanced colorectal cancer. Its detection is thought to have prognostic significance and it is being considered to predict responsiveness to anti-EGFR therapy. Unfortunately, while immunohistochemical assessment of PTEN expression is widespread, it lacks standardization and the results are hardly comparable across the available publications. METHODS: Retrospectively collected, formalin-fixed and paraffin-embedded colorectal tumor tissue samples from 55 patients were combined into tissue microarray (TMA) blocks. We used three different PTEN antibodies to determine the frequency, intensity and intracellular pattern of PTEN immunohistochemical labeling: Neomarkers, Dako and CellSignaling. We evaluated the aforementioned parameters in selected regions of colorectal cancers and in their lymph node metastases by using three scoring methods that take into consideration both staining frequency and intensity (H1-H3-score). We also evaluated intracellular localization. RESULTS: The Dako and CellSignaling antibodies stained predominantly cytoplasms, while the Neomarkers antibody specifically stained cell nuclei. PTEN H-scores were significantly lower in all tumor areas as compared to the normal colonic mucosa based on staining with the DAKO and CellSignaling antibodies. Intratumoral regional differences or differences between matching tumors and metastases were not detected with any of the antibodies. Neither Dako, neither CellSignaling, nor the Neomarkers antibodies revealed a significant correlation between PTEN expression and pT, Dukes/MAC and clinical stage. KRAS status, histological grade correlated with PTEN H-scores based on staining with the Neomarkers antibody. PTEN H-scores did not correlate with MMR status. PTEN H-scores did not show any correlation with relapse-free survival based on staining with either antibody. CONCLUSIONS: While PTEN expression decreased in colorectal cancer according to two antibodies, neither of the three applied PTEN antibodies could justify significant correlation with clinicopathological data, nor had prognostic value. Thus, we might conclude that immunohistochemical PTEN investigation remains a challenge requiring more standardized evaluation on larger number of cases to clarify its utility as a prognostic and predictive tool in CRC. The standardization of immunohistochemical method is key in the evaluation process, which is further discussed

Urinary Free Glycosaminoglycans Identify Adults at High Risk of Developing Early-stage High-grade Bladder Cancer

Background and objective: Screening for bladder cancer (BCa) could reduce mortality via early detection of early-stage high-grade (Ta/T1 N0 M0 grade 2-3) disease. Noninvasive biomarkers could aid in screening, but current markers lack the specificity required. The urinary free glycosaminoglycan profile (GAGome) is a promising biomarker for early detection of BCa metabolism. Methods: In a prospective case-control development study, we included patients with BCa or no evidence of disease (NED) and measured the urinary GAGome. We then developed a score to predict the probability of BCa using GAGome features that correlated with BCa versus NED according to Bayesian regression. Next, in a retrospective, population-based, case-control study, we included adults from the Lifelines Cohort Study who were presumed healthy at baseline. All cases with BCa confirmed in the cancer registry by the 2-yr or 6-yr study visit were matched to randomly selected control subjects. We developed a reference logistic regression model using age and sex to predict BCa at 7 yr after baseline. We then added the GAGome score to the model and assessed model improvement using the likelihood ratio test. We dichotomized outputs for the reference model and saturated model (reference + GAGome score) into high-risk versus low-risk categories using a 99% specificity cutoff and estimated the sensitivity for association with BCa at 7 yr. Key findings and limitations: We prospectively included 51 individuals with BCa and 38 with NED and observed alterations in three GAGome features compatible with BCa. We developed a score that discriminated BCa with an area under the receiver operating characteristic curve of 0.77 (95% confidence interval [CI] 0.67-0.87). We retrospectively selected a cohort of 1088 presumed healthy adults (median age 48 yr, 56% females), of whom 48 had developed BCa by 7 yr after baseline (median time to diagnosis 1.4 yr). The GAGome score was an independent predictor of BCa at 7 yr when added to the reference model (p &lt; 0.001). The sensitivity for BCa at 7 yr for high-risk subjects was 31% (95% CI 20-43%) using the saturated model and 17% (95% CI 4.7-29%) using the reference model at 99% specificity (95% CI 98-99%). Conclusions and clinical implications: The urinary free GAGome is specifically altered in BCa and can be used for noninvasive identification of adults at high risk of developing BCa, independent of age and sex. This information could be useful for the design of risk-stratified targeted screening programs for BCa. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/)

Caveat Emptor, Computational Social Science: Large-Scale Missing Data in a Widely-Published Reddit Corpus

As researchers use computational methods to study complex social behaviors at scale, the validity of this computational social science depends on the integrity of the data. On July 2, 2015, Jason Baumgartner published a dataset advertised to include ``every publicly available Reddit comment'' which was quickly shared on Bittorrent and the Internet Archive. This data quickly became the basis of many academic papers on topics including machine learning, social behavior, politics, breaking news, and hate speech. We have discovered substantial gaps and limitations in this dataset which may contribute to bias in the findings of that research. In this paper, we document the dataset, substantial missing observations in the dataset, and the risks to research validity from those gaps. In summary, we identify strong risks to research that considers user histories or network analysis, moderate risks to research that compares counts of participation, and lesser risk to machine learning research that avoids making representative claims about behavior and participation on Reddit

Analyzing Users' Activity in On-line Social Networks over Time through a Multi-Agent Framework

[EN] The number of people and organizations using online social networks as a new way of communication is continually increasing. Messages that users write in networks and their interactions with other users leave a digital trace that is recorded. In order to understand what is going on in these virtual environments, it is necessary systems that collect, process, and analyze the information generated. The majority of existing tools analyze information related to an online event once it has finished or in a specific point of time (i.e., without considering an in-depth analysis of the evolution of users activity during the event). They focus on an analysis based on statistics about the quantity of information generated in an event. In this article, we present a multi-agent system that automates the process of gathering data from users activity in social networks and performs an in-depth analysis of the evolution of social behavior at different levels of granularity in online events based on network theory metrics. We evaluated its functionality analyzing users activity in events on Twitter.This work is partially supported by the PROME-TEOII/2013/019, TIN2014-55206-R, TIN2015-65515-C4-1-R, H2020-ICT-2015-688095.Del Val Noguera, E.; Martínez, C.; Botti, V. (2016). Analyzing Users' Activity in On-line Social Networks over Time through a Multi-Agent Framework. Soft Computing. 20(11):4331-4345. https://doi.org/10.1007/s00500-016-2301-0S433143452011Ahn Y-Y, Han S, Kwak H, Moon S, Jeong H (2007) Analysis of topological characteristics of huge online social networking services. 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Identification and characterization of extensive intra-molecular associations between 3′-UTRs and their ORFs

During eukaryotic translation, mRNAs may form intra-molecular interactions between distant domains. The 5′-cap and the polyA tail were shown to interact through their associated proteins, and this can induce physical compaction of the mRNA in vitro. However, the stability of this intra-molecular association in translating mRNAs and whether additional contacts exist in vivo are largely unknown. To explore this, we applied a novel approach in which several endogenous polysomal mRNAs from Saccharomyces cerevisiae were cleaved near their stop codon and the resulting 3′-UTR fragments were tested either for co-sedimentation or co-immunoprecipitation (co-IP) with their ORFs. In all cases a significant fraction of the 3′-UTR fragments sedimented similarly to their ORF-containing fragments, yet the extent of co-sedimentation differed between mRNAs. Similar observations were obtained by a co-IP assay. Interestingly, various treatments that are expected to interfere with the cap to polyA interactions had no effect on the co-sedimentation pattern. Moreover, the 3′-UTR appeared to co-sediment with different regions from within the ORF. Taken together, these results indicate extensive physical associations between 3′-UTRs and their ORFs that vary between genes. This implies that polyribosomal mRNAs are in a compact configuration in vivo