bluuebunny/crossref_metadata_2025 huggingface dataset:
A response to criticisms on “CMB constraints cast a shadow on CSL model”
Authors: Martin Jérôme , Vennin Vincent
Published: January 2021

Our recent letter “Cosmic Microwave Background Constraints Cast a Shadow On Continuous Spontaneous Localization Models” (Martin and Vennin Phys Rev Lett 124:080402, 2020, arXiv:1906.04405) has recently been criticised in Ref. (Bengochea et al. Eur Phys J C 80:1021, 2020a) (see also Ref. Bengochea et al. 2020b, arXiv:2006.05313). In this reply, we explain why the arguments presented in those articles are either incorrect or a confirmation of the robustness of our results.
Short-scale quantum kinetic theory including spin–orbit interactions
Authors: Ekman R. , Al-Naseri H. , Zamanian J. , Brodin G.
Published: January 2021

We present a quantum kinetic theory for spin-1/2 particles, including the spin–orbit interaction, retaining particle dispersive effects to all orders in $$\hbar $$
ħ
, based on a gauge-invariant Wigner transformation. Compared to previous works, the spin–orbit interaction leads to a new term in the kinetic equation, containing both the electric and magnetic fields. Like other models with spin–orbit interactions, our model features “hidden momentum”. As an example application, we calculate the dispersion relation for linear electrostatic waves in a magnetized plasma, and electromagnetic waves in a unmagnetized plasma. In the former case, we compare the Landau damping due to spin–orbit interactions to that due to the free current. We also discuss our model in relation to previously published works.

Graphic abstract
Nonlinear Interval Optimization of Asymmetric Damper Parameters for a Racing Car
Authors: Chai Tian , Han Xu , Liu Jie , Zhou Bing , Lei Fei , Li Fan
Published: January 2021

Uncertainties in parameters can affect racing car performance. In this study, a nonlinear interval suspension damping optimization method is proposed to improve the road holding of a racing car. To evaluate the dynamic responses of racing cars under a random road input and a bump input with interval uncertain parameters, a quarter car model with a two-stage asymmetric damper is established. Then, a quadratic approximation model with second derivative terms is developed by second-order Taylor series expansion and dimension reduction to calculate the nonlinear dynamic response of the vehicle. Interval analysis of the objective function and constraints is carried out using interval arithmetic to eliminate nesting optimization and make the optimization efficient. The results show that the proposed optimization method can improve road holding performance, effectively suppress the fluctuation range of the road holding performance evaluation index, and ensure the robustness of the design scheme.
Location- and Person-Independent Activity Recognition with WiFi, Deep Neural Networks, and Reinforcement Learning
Authors: Ma Yongsen , Arshad Sheheryar , Muniraju Swetha , Torkildson Eric , Rantala Enrico , Doppler Klaus , Zhou Gang
Published: January 2021

In recent years, Channel State Information (CSI) measured by WiFi is widely used for human activity recognition. In this article, we propose a deep learning design for location- and person-independent activity recognition with WiFi. The proposed design consists of three Deep Neural Networks (DNNs): a 2D Convolutional Neural Network (CNN) as the recognition algorithm, a 1D CNN as the state machine, and a reinforcement learning agent for neural architecture search. The recognition algorithm learns location- and person-independent features from different perspectives of CSI data. The state machine learns temporal dependency information from history classification results. The reinforcement learning agent optimizes the neural architecture of the recognition algorithm using a Recurrent Neural Network (RNN) with Long Short-Term Memory (LSTM). The proposed design is evaluated in a lab environment with different WiFi device locations, antenna orientations, sitting/standing/walking locations/orientations, and multiple persons. The proposed design has 97% average accuracy when testing devices and persons are not seen during training. The proposed design is also evaluated by two public datasets with accuracy of 80% and 83%. The proposed design needs very little human efforts for ground truth labeling, feature engineering, signal processing, and tuning of learning parameters and hyperparameters.
Attack Context Embedded Data Driven Trust Diagnostics in Smart Metering Infrastructure
Authors: Bhattacharjee Shameek , Madhavarapu Venkata Praveen Kumar , Silvestri Simone , Das Sajal K.
Published: January 2021

Spurious power consumption data reported from compromised meters controlled by organized adversaries in the Advanced Metering Infrastructure (AMI) may have drastic consequences on a smart grid’s operations. While existing research on data falsification in smart grids mostly defends against isolated electricity theft, we introduce a taxonomy of various data falsification attack types, when smart meters are compromised by organized or strategic rivals. To counter these attacks, we first propose a
coarse-grained and a fine-grained anomaly-based security event detection technique
that uses indicators such as deviation and directional change in the time series of the proposed anomaly detection metrics to indicate: (i) occurrence, (ii) type of attack, and (iii) attack strategy used, collectively known as
attack context
. Leveraging the attack context information, we propose three
attack response metrics
to the inferred attack context: (a) an unbiased mean indicating a robust location parameter; (b) a median absolute deviation indicating a robust scale parameter; and (c) an attack probability time ratio metric indicating the active time horizon of attacks. Subsequently, we propose a trust scoring model based on
Kullback-Leibler (KL)
divergence, that embeds the appropriate unbiased mean, the median absolute deviation, and the attack probability ratio metric at runtime to produce trust scores for each smart meter. These trust scores help classify compromised smart meters from the non-compromised ones. The embedding of the attack context, into the trust scoring model, facilitates accurate and rapid classification of compromised meters, even under large fractions of compromised meters, generalize across various attack strategies and margins of false data. Using real datasets collected from two different AMIs, experimental results show that our proposed framework has a high true positive detection rate, while the average false alarm and missed detection rates are much lesser than 10% for most attack combinations for two different real AMI micro-grid datasets. Finally, we also establish fundamental theoretical limits of the proposed method, which will help assess the applicability of our method to other domains.
Polynomial-Time Random Oracles and Separating Complexity Classes
Authors: Hitchcock John M. , Sekoni Adewale , Shafei Hadi
Published: January 2021

Bennett and Gill [1981] showed that P

A

≠ NP

A

≠ coNP

A

for a random oracle
A
, with probability 1. We investigate whether this result extends to individual polynomial-time random oracles. We consider two notions of random oracles: p-random oracles in the sense of martingales and resource-bounded measure [Lutz 1992; Ambos-Spies et al. 1997], and p-betting-game random oracles using the betting games generalization of resource-bounded measure [Buhrman et al. 2000]. Every p-betting-game random oracle is also p-random; whether the two notions are equivalent is an open problem.

(1) We first show that P

A

≠ NP

A

for every oracle
A
that is p-betting-game random.

Ideally, we would extend (1) to p-random oracles. We show that answering this either way would imply an unrelativized complexity class separation:

(2) If P

A

≠ NP

A

relative to every p-random oracle
A
, then BPP ≠ EXP.

(3) If P

A

≠ NP

A

relative to some p-random oracle
A
, then P ≠ PSPACE.

Rossman, Servedio, and Tan [2015] showed that the polynomial-time hierarchy is infinite relative to a random oracle, solving a longstanding open problem. We consider whether we can extend (1) to show that PH

A

is infinite relative to oracles
A
that are p-betting-game random. Showing that PH

A

separates at even its first level would also imply an unrelativized complexity class separation:

(4) If NP

A

≠ coNP

A

for a p-betting-game measure 1 class of oracles
A
, then NP ≠ EXP.

(5) If PH

A

is infinite relative to every p-random oracle
A
, then PH ≠ EXP.

We also consider random oracles for time versus space, for example:

(6) L

A

≠ P

A

relative to every oracle
A
that is p-betting-game random.
Computational and Proof Complexity of Partial String Avoidability
Authors: Itsykson Dmitry , Okhotin Alexander , Oparin Vsevolod
Published: January 2021

The partial string avoidability problem is stated as follows: given a finite set of strings with possible “holes” (wildcard symbols), determine whether there exists a two-sided infinite string containing no substrings from this set, assuming that a hole matches every symbol. The problem is known to be NP-hard and in PSPACE, and this article establishes its PSPACE-completeness. Next, string avoidability over the binary alphabet is interpreted as a version of conjunctive normal form satisfiability problem, where each clause has infinitely many shifted variants. Non-satisfiability of these formulas can be proved using variants of classical propositional proof systems, augmented with derivation rules for shifting proof lines (such as clauses, inequalities, polynomials, etc.). First, it is proved that there is a particular formula that has a short refutation in Resolution with a shift rule but requires classical proofs of exponential size. At the same time, it is shown that exponential lower bounds for classical proof systems can be translated for their shifted versions. Finally, it is shown that superpolynomial lower bounds on the size of shifted proofs would separate NP from PSPACE; a connection to lower bounds on circuit complexity is also established.
Clinical Neuroscience of Addiction: What Clinical Psychologists Need to Know and Why
Authors: Ray Lara A. , Grodin Erica N.
Published: January 2021

The last three decades in psychological research have been marked by interdisciplinary science. Addiction represents a prime example of a disorder marked by a complex interaction among psychosocial and biological factors. This review highlights critical findings in the basic neuroscience of addiction and translates them into clinical language that can inform clinical psychologists in their research, teaching, and practice. From mechanisms of reward processing, learning and memory, allostasis, incentive-sensitization, withdrawal, tolerance, goal-directed decision making, habit learning, genetics, inflammation, and the microbiome, the common theme of this review is to illustrate the clinical utility of basic neuroscience research and to identify opportunities for clinical science. The thoughtful integration of basic and clinical science provides a powerful tool to fulfill the scientific mission of improving health care. Clinical psychologists have a crucial role to play in the translational science of addiction.
The Shaping of a B Cell Pool Maximally Responsive to Infections
Authors: Baumgarth Nicole
Published: January 2021

B cell subsets differ in development, tissue distribution, and mechanisms of activation. In response to infections, however, all can differentiate into extrafollicular plasmablasts that rapidly provide highly protective antibodies, indicating that these plasmablasts are the main humoral immune response effectors. Yet, the effectiveness of this response type depends on the presence of antigen-specific precursors in the circulating mature B cell pool, a pool that is generated initially through the stochastic processes of B cell receptor assembly. Importantly, germinal centers then mold the repertoire of this B cell pool to be increasingly responsive to pathogens by generating a broad array of antimicrobial memory B cells that act as highly effective precursors of extrafollicular plasmablasts. Such B cell repertoire molding occurs in two ways: continuously via the chronic germinal centers of mucosal lymphoid tissues, driven by the presence of the microbiome, and via de novo generated germinal centers following acute infections. For effectively evaluating humoral immunity as a correlate of immune protection, it might be critical to measure memory B cell pools in addition to antibody titers.
Platinum Nanoarrays Directly Grown onto a 3D-Carbon Felt Electrode as a Bifunctional Material for Garden Compost Microbial Fuel Cell
Authors: Kosimaningrum Widya Ernayati , Ouis Mekhaissia , Holade Yaovi , Buchari Buchari , Noviandri Indra , Kameche Mostefa , Cretin Marc , Innocent Christophe
Published: January 2021

The practical implementation of air-breathing microbial fuel cell (MFC) is critically linked to the development of efficient materials as cathode and electrochemically active biofilm-based anode. In this contribution, we demonstrate the feasibility by decorating a 3D carbon felt electrode with Pt nanoarrays (CF@Pt) as a bifunctional electrode material as efficient garden compost bioanode and air-breathing cathode. Half-cell electrochemical characterizations reveal that the onset potential of the anode reaction negatively shifts of about 800 mV to reach −0.4 V vs Ag/AgCl after the growth of the biofilm onto CF@Pt. The investigation before and after the biofilm formation shows that Pt nanoarrays act as excellent electron relays, reducing significantly the charge transfer resistance. For MFC application (with a proton exchange membrane), the use of CF@Pt as bioanode’ scaffold and CF@Pt air-cathode enables a drastically enhanced power density of Pmax = 292.3 mW m−2, and a high short-circuit current density jsc = 1.9 A m−2.
Effects of inorganic nitrate supplementation on cardiovascular function and exercise tolerance in heart failure
Authors: Ferguson Scott K. , Woessner Mary N. , Holmes Michael J. , Belbis Michael D. , Carlström Mattias , Weitzberg Eddie , Allen Jason D. , Hirai Daniel M.
Published: January 2021

Heart failure (HF) results in a myriad of central and peripheral abnormalities that impair the ability to sustain skeletal muscle contractions and, therefore, limit tolerance to exercise. Chief among these abnormalities is the lowered maximal oxygen uptake, which is brought about by reduced cardiac output and exacerbated by O2delivery-utilization mismatch within the active skeletal muscle. Impaired nitric oxide (NO) bioavailability is considered to play a vital role in the vascular dysfunction of both reduced and preserved ejection fraction HF (HFrEF and HFpEF, respectively), leading to the pursuit of therapies aimed at restoring NO levels in these patient populations. Considering the complementary role of the nitrate-nitrite-NO pathway in the regulation of enzymatic NO signaling, this review explores the potential utility of inorganic nitrate interventions to increase NO bioavailability in the HFrEF and HFpEF patient population. Although many preclinical investigations have suggested that enhanced reduction of nitrite to NO in low Po2and pH environments may make a nitrate-based therapy especially efficacious in patients with HF, inconsistent results have been found thus far in clinical settings. This brief review provides a summary of the effectiveness (or lack thereof) of inorganic nitrate interventions on exercise tolerance in patients with HFrEF and HFpEF. Focus is also given to practical considerations and current gaps in the literature to facilitate the development of effective nitrate-based interventions to improve exercise tolerance in patients with HF.
Ki67 Predicts Progression in Early CIN: Validation of a Multivariate Progression‐Risk Model
Authors: Kruse Arnold-Jan , Baak Jan P. A. , Janssen Emiel A. , Kjellevold Kjell-Henning , Fianec Bent , Lovslett Kjell , Bergh Johan , Robboy Stanley
Published: January 2021

This study of early CIN biopsies (25 CIN1 and 65 CIN2) with long follow‐up was done to validate, in a new group
of patients, the value of Ki67 immuno‐quantitative features to predict high CIN grade in a follow‐up biopsy (often denoted to as
“progression”), as described in a previous study. Each biopsy in the present study was classified with the previously described
Ki67‐model (consisting of the stratification index and the % positive nuclei in the middle third layer of the epithelium) as
“low‐risk” or “high‐risk”, and matched with the follow‐up outcome (progression‐or‐not). Furthermore, it was studied whether
subjective evaluation of the Ki67 sections by experienced pathologists, who were aware of the prognostic quantitative Ki67
features, could also predict the outcome. Thirdly, the reproducibility of routine use of the quantitative Ki67‐model was assessed.
Fifteen cases progressed (17%) to CIN3, 2/25 CIN1 (8%) and 13/65 CIN2 (20%), indicating that CIN grade (as CIN1 or CIN2) is
prognostic and that the percentage of CIN1 and CIN2 cases with progression in the present study is comparable to many previous
studies. However, the quantitative Ki67 model had stronger prognostic value than CIN grade as none of the 40 “Ki67‐model
low‐risk” patients progressed, in contrast to 15 (30%) of the 50 “Ki67‐model high‐risk” patients (p < 0.001). In multivariate
analysis, neither CIN grade nor any of the other quantitative Ki67 features added to the abovementioned prognostic Ki67‐model.
Subjective analysis of the Ki67 features was also prognostic, although quantitative assessments gave better results. Routine
application of the quantitative Ki67‐model in CIN1 and CIN2 was well reproducible. In conclusion, the results confirm that
quantitative Ki67 features have strong prognostic value for progression in early CIN lesions.
Interobserver Reproducibility of Dna‐Image‐Cytometry in Ascus or Higher Cervical Cytology
Authors: Nguyen Vu Quoc Huy , Grote Hans Jürgen , Pomjanski Natalia , Knops Kristiane , Böcking Alfred
Published: January 2021

In the present study, the aim has been to investigate the interobserver reproducibility of DNA‐image‐cytometry (DNA‐ICM) applied to routine Pap smears classified as Atypical Squamous Cells of Undetermined Significance (ASCUS) or higher lesions (ASCUS+). 202 Pap smears diagnosed as ASCUS or higher were included in the study. After cytological assessment, smears underwent restaining according to Feulgen. First measurements were performed as routine workup. The second measurements were blinded to the result of the first and consecutively performed. DNA‐ICM met the consensus statements of the European Society of Analytical Cellular Pathology (ESACP). Interobserver agreement was assessed by calculating Kappa statistics. The diagnosis of DNA‐aneuploidy in the first measurements was confirmed in all cases. Second measurement detected 12 additional cases with aneuploidy. Nine out of these cases were classified as aneuploidy by detection of 9c Exceeding Events (9cEE). In three cases stemline‐aneuploidy was disclosed. The overall proportion of observed agreement was 94.1%, κ=0.87, 95% CI=0.74–0.99. Our study shows a good interobserver reproducibility of DNA‐ICM performed on cervical smears with ASCUS or higher lesions. DNA‐ICM thus represents a highly reproducible diagnostic procedure.
Proliferation in Non‐Hodgkin’S Lymphomas and Its Prognostic Value Related to Staging Parameters
Authors: Lorand‐Metze Irene , Pereira Fernanda Gonçalves , Costa Flávia Pereira Silva , Metze Konradin
Published: January 2021

In malignant lymphomas, cell kinetics has shown to be related with histologic type as well as with the clinical behaviour. The aim of our study was to investigate the relevance of cell proliferation parameters on overall survival in non‐Hodgkin′s lymphomas as well as their relationship with prognostic factors such as International Prognostic Index (IPI). We performed DNA‐flow‐cytometry (S‐phase fraction and detection of DNA‐aneuploidy) as well as cytologic examination and the AgNOR technique in material obtained by fine needle aspiration of lymph nodes at diagnosis. The majority of the patients were stage IV by Ann Arbor and intermediate risk by IPI (42/55). When analyzing all patients together, histologic type by the WHO classification, IPI and the presence of a DNA‐aneuploid clone could not separate well patients with a different survival. For all patients, univariate Cox analysis revealed S‐phase (SPF) and AgNOR parameters to be of prognostic value. In the multivariate analysis, however, only SPF remained in the final model. Yet, when stratifying for DNA‐ploidy, only the total number of AgNORs/nucleus was an independent parameter. Looking only at the DNA‐diploid cases, the AgNOR pattern remained the most important parameter, whereas for the DNA‐aneuploid cases this was true for SPF. When studying patients with B large cell lymphoma separately, only DNA‐ploidy was a prognostic factor. In summary, cell kinetic parameters reveal important prognostic information in NHL patients. Furthermore, DNA‐aneuploidy seems to interfere with the analysis of the AgNOR pattern.
The Relationship between Syntactic Structure Analysis Features, Histological Grade and High‐Risk HPV DNA in Cervical Intraepithelial Neoplasia
Authors: Kruse Arnold‐Jan , Buhr‐Wildhagen Susanne , Janssen Emiel A. , Baak Jan P.A.
Published: January 2021

Aim: To assess the correlation between syntactic structure analysis (SSA) features, revised dysplasia grade and the presence of high‐risk human papillomavirus DNA in cervical intraepithelial neoplasia (CIN). Materials and methods: HPV polymerase chain reaction (PCR) was assessed in 101 consecutive biopsies and consensus in CIN grade between the experts occurred in 88 cases (CIN1=16, CIN2=27, CIN3=45). SSA was performed in the diagnostic histological section of the CIN lesions in these patients and SSA features were compared with the blind review CIN grade, and presence/absence of high‐risk HPV DNA. Results: One of the SSA features (points from which the surrounding surfaces has 4 edges, PECO‐4) was significantly different between all three consensus CIN grades. Many more features revealed significant differences between CIN1 and CIN2 or between CIN2 and CIN3 cases. With stepwise discriminant analysis, the best multivariate combination of features to distinguish the different CIN grades were the Maximum MST Line Length (MML) and the Area Disorder. Crude overall classification of the consensus grades with these features was 69%. The MML and the Area Disorder is also the best combination to distinguish cases with and without high‐risk HPV DNA (77% correct classifications). Conclusions: SSA features are correlated with both CIN grade and presence of high‐risk HPV DNA, but the discrimination power is not good enough to be used as a routine method for quality control of subjective grade or as a surrogate marker for high‐risk HPV DNA presence.
Report on the Dutch Consensus Development Meeting for Implementation and Further Development of Population Screening for Colorectal Cancer Based on FOBT
Authors: de Visser M. , van Ballegooijen M. , Bloemers S. M. , van Deventer S. J. H. , Jansen J. B. M. J. , Jespersen J. , Kluft C. , Meijer G. A. , Stoker J. , de Valk G. A. , Verweij M. F. , Vlems F. A.
Published: January 2021

A consensus development meeting was held to evaluate whether or not in the Netherlands all requirements were fulfilled for implementation of population screening with FOBT for colorectal cancer, or whether consensus was present that fulfilment by additional research or organisational actions could be obtained within 2–3 years. There was consensus that all classical Wilson and Jungner (1968) criteria, and six additional ones added more recently, had already been fulfilled or could be fulfilled within 2–3 years. Consequently, it was concluded that a national population screening for colorectal cancer should be implemented and carried out in the Netherlands in line with current national and European cancer screening programmes. A list of organisational actions to be taken was established. Research that is needed before the actual national launch of the screening within 2–3 years has been defined. Priorities have to be set for research and organisational actions for the coming 2–3 years for the implementation of population screening. In addition, research suggestions have been defined for the next 10–15 years for evaluation and/or improvement of implemented FOBT screening, and for future screening methodology. It was considered essential that infrastructure for future research would be embedded in the screening programme. A project group to arrange this should be formed.
Molecular Characterization of PDGFR‐α/PDGF‐A and c‐KIT/SCF in Gliosarcomas
Authors: Reis Rui M. , Martins Albino , Ribeiro Susana A. , Basto Diana , Longatto-Filho Adhemar , Schmitt Fernando C. , Lopes José M.
Published: January 2021

Gliosarcomas are rare and poorly characterized malignant brain tumors that exhibit a biphasic tissue pattern with areas of gliomatous and sarcomatous differentiation. These tumors are histological variants of glioblastoma, displaying a similar genetic profile and dismal prognosis. Up‐regulation of PDGFR subfamily of tyrosine kinase members, PDGFR‐α and c‐Kit, and their intracellular effectors RAS/RAF/MAPK has a crucial role in the cancer development. In addition, signal transduction mediated by activating mutations of c‐Kit and PDGFR can be effectively blocked by specific tyrosine kinase inhibitors, such as Imatinib mesylate. The aim of this study was to characterize the molecular alterations of PDGFR signaling in gliosarcomas. Six cases were analyzed by immunohistochemistry for the expression of PDGFR‐α, c‐Kit and their ligands PDGF‐A and SCF, respectively. The cases were further evaluated for the presence of activating mutations of PDGFR‐α (exons 12 and 18) and c‐kit (exons 9, 11, 13, and 17), as well as B-RAF (exons 11 and 15). Expression of PDGF‐A was found in all cases and co‐expression of PDGFR‐α was observed in three cases. Four cases showed expression of SCF, and c‐Kit was observed only in one case that also expressed SCF. Generally, immunoreaction predominates in the glial component. The mutational analysis of PDGFR‐α showed the presence of an IVS17‐50insT intronic insertion in two cases, one of them also with a 2472C > T silent mutation; this silent mutation was also found in another case. Glioma cell line analysis of IVS17‐50insT insertion showed no influence on PDGFR‐α gene splicing. No mutations were detected in c‐kit and B-RAF oncogenes. Our Results indicate that activating mutations of PDGFR‐α, c‐kit and B-RAF are absent in gliosarcomas. Nevertheless, the presence of a PDGFR‐a/PDGFA and c‐Kit/SCF autocrine/paracrine stimulation loop in a proportion of cases, supports the potential role of specific tyrosine kinase inhibitors in the treatment of gliosarcomas.
Chromosomal Changes in relation to Clinical Outcome in Larynx and Pharynx Squamous Cell Carcinoma
Authors: Hermsen Mario , Alonso Guervós Marta , Meijer Gerrit , van Diest Paul , Suárez Nieto Carlos , Marcos Cesar Alvarez , Sampedro Andrés
Published: January 2021

Invasive head and neck squamous carcinomas are among the cytogenetically most complex tumors. Perhaps for this reason, there is little consensus on the prognostic value of specific chromosomal aberrations. Here we present Results of CGH analysis of 56 clinically well‐characterized set of head and neck cancers, consisting of larynx and pharynx only. The aim was to find possible associations with clinical outcome. The major chromosome arms showing gains were (in decreasing order): 3q, 7q, 8q, 5p, 11q13, 17q and 18p, and losses occurred at 3p, 11qter, 4p, 18q, and 5q. The segments most frequently amplified were 3q26‐qter, 11q13, 11q22, 3q12–13, 18p11.3, 18q11.2 and 8q24.3. Tumors with stages III and IV, and lymph node positive tumors had a worse clinical outcome. Surprisingly, no specific chromosomal abnormality correlated with disease‐free survival. The only aberration that correlated to one of the clinico‐pathological parameters was amplification 11q13, that occurred solely in lymph node positive, stage IV tumors. However 11q13 amplification did not correlate with disease‐free survival. These Results seem to indicate that genetic alterations at the level of chromosomes have limited prognostic value in patients with invasive larynx and pharynx squamous cell carcinomas.
Development of 3D Chromatin Texture Analysis Using Confocal Laser Scanning Microscopy
Authors: Huisman André , Ploeger Lennert S. , Dullens Hub F. J. , Poulin Neal , Grizzle William E. , van Diest Paul J.
Published: January 2021

Introduction: Analysis of nuclear texture features as a measure of nuclear chromatin changes has been proven to be useful when measured on thin (5–6 μm) tissue sections using conventional 2D bright field microscopy. The drawback of this approach is that most nuclei are not intact because of those thin sections. Confocal laser scanning microscopy (CLSM) allows measurements of texture in 3D reconstructed nuclei. The aim of this study was to develop 3D texture features that quantitatively describe changes in chromatin architecture associated with malignancy using CLSM images. Methods: Thirty‐five features thoughtfully chosen from 4 categories of 3D texture features (discrete texture features, Markovian features, fractal features, grey value distribution features) were selected and tested for invariance properties (rotation and scaling) using artificial images with a known grey value distribution. The discriminative power of the 3D texture features was tested on artificially constructed benign and malignant 3D nuclei with increasing nucleolar size and advancing chromatin margination towards the periphery of the nucleus. As a clinical proof of principle, the discriminative power of the texture features was assessed on 10 benign and 10 malignant human prostate nuclei, evaluating also whether there was more texture information in 3D whole nuclei compared to a single 2D plane from the middle of the nucleus. Results: All texture features showed the expected invariance properties. Almost all features were sensitive to variations in the nucleolar size and to the degree of margination of chromatin. Fourteen texture features from different categories had high discriminative power for separating the benign and malignant nuclei. The discrete texture features performed less than expected. There was more information on nuclear texture in 3D than in 2D. Conclusion: A set of 35 3D nuclear texture features was used successfully to assess nuclear chromatin patterns in 3D images obtained by confocal laser scanning microscopy, and as a proof of principle we showed that these features may be clinically useful for analysis of prostate neoplasia.
p53, Bcl‐2 and C‐Myc Expressions in Colorectal Carcinoma Associated with Schistosomiasis in Egypt
Authors: Zalata Khaled R. , Nasif Wesam A. , Ming Si-Chun , Lotfy Mahmoud , Nada Nadia A. , El-Hak Nabil Gad , Leech Stephen H.
Published: January 2021

Background and Aims: Oncogenes and tumor suppressor genes expression are well described in bladder cancer associated with schistosomiasis especially in Egypt. Scarce studies were directed to colorectal cancer (CRC) associated with Schistosoma mansoni (S. mansoni). Apoptosis (programmed cell death) and the genes regulating this process (e.g., Bcl‐2) have recently become a focus of interest in the study of cancer development and progression. In the present study, we aimed to investigate the expression pattern of p53, Bcl‐2 and C‐Myc in CRC tissues obtained from Egyptian colorectal cancer patients divided in two different groups, one associated with Schistosoma mansoni (CRC‐Sm) and the other without Schistosoma mansoni (CRC‐NSm). Methods: Seventy‐five CRC tumors containing 36 draining lymph node metastatic tumors were immunohistochemically stained using specific monoclonal antibodies for p53, Bcl‐2 and C‐Myc, in addition the apoptotic activity of these tumors were analyzed. Results and Conclusions: Regardless of the S. mansoni infection, the obtained Results showed that the apoptotic activity was more evident in p53 diffuse positive tumors (P=0.021). There was a significant correlation between p53 diffuse positive staining and Bcl‐2 positive immunostaining (P=0.011). Signet ring cell carcinoma and mucinous adenocarcinoma exhibited both intense C‐Myc expression than non‐mucinous carcinoma (P=0.001). When adjusting for S. mansoni infection, 58.3% of CRC‐Sm cases were Bcl‐2 positive compared to only (33.3%) of CRC‐NSm (P=0.046). Apoptotic activity was more evident in the latter group than of CRC‐Sm tumors (P=0.009). p53 and C‐Myc expressions were found insignificantly different in CRC‐Sm compared with CRC‐NSm (P>0.05). These observations suggest that the genotoxic agents produced endogenously through the course of schistosomiasis mansoni may play a role in CRC‐Sm pathogenesis through the dysregulation of apoptosis by alteration the expression pattern of Bcl‐2 protein differently from CRC‐NSm suggesting a different biological behavior.
The Role of Macrophages in Tumor Development
Authors: van der Bij Gerben J. , Oosterling Steven J. , Meijer Sybren , Beelen Robert H. J. , van Egmond Marjolein
Published: January 2021

Macrophages constitute a large proportion of the immune cell infiltrate, which is present in many tumors. Activation state of macrophages is greatly influenced by their environment, leading to different macrophage subsets with diverse functions. Although previously regarded as potent immune cells that are capable of destroying tumor cells, recent literature focuses on the ability of macrophages to promote tumor development due to secretion of mediators, like growth and angiogenic factors. It is now becoming increasingly clear that a complicated synergistic relationship exists between macrophages and malignant cells whereby tumor cells can affect macrophage phenotype, and vice versa. As such, macrophages and their contribution in cancer development are currently subject of debate.
Success Predictors of Adjuvant Chemotherapy in Node‐Negative Breast Cancer Patients Under 55 years1
Authors: Janssen Emiel A. M. , van Diest Paul J. , Søiland Håvard , Gudlaugson Einar , Nysted Arne , Voorhorst Feja J. , Vermorken Jan B. , Søreide Jon-Arne , Baak Jan P. A.
Published: January 2021

Background: Adjuvant systemic chemotherapy (ASCT) in lymph node‐negative breast (LN−) cancers improves survival. The majority of (LN−) patients receive ASCT when the St. Gallen criteria or its modifications are used, as accurate identifiers which patients benefit from ASCT are lacking. This may imply over‐treatment in many patients. Aim: To evaluate which patients or primary tumor factors predict ASCT success. Material and method: Retrospective analysis by single and multivariate survival analysis of clinical and tumor characteristics in (LN−) breast cancers <55 years, related to ASCT (n = 125) or‐not (n = 516). Results: The two patient groups did not differ in age, tumor diameter, grade, type, number of mitoses and other factors. Fourteen‐year survival for the ASCT and non‐ASCT patients was 83% and 74% (Hazard Ratio = HR = 0.33; p < 0.0001, 9% absolute = 12% relative difference). Subgroup analysis showed that the recurrence‐free survival = RFS of ASCT treated vs. non‐treated patients differed in patients with grade 1 cancers (p = 0.008), grade 2 cancers (p = 0.004), grades 3 (p = 0.02), tumors under and ≧2 cm (p = 0.001 and 0.0002), oestrogen receptor‐positive or ‐negative tumors (p = 0.003, 0.04), MAI < 10 and ≧10 (p = 0.005, 0.003) and fibrotic focus absent (p = 0.002). With multivariate analysis the most important predictor of ASCT effect was the MAI. In patients with slowly proliferating tumors (MAI < 3) no advantage was found between patients treated‐or‐not with adjuvant chemotherapy (RFS = 92% and 91%, p = 0.13, p = 0.63 for overall survival), contrasting those with MAI ≧ 3 (p = 0.0001; HR = 0.32, 95% CI 0.18–0.58). Conclusion: MAI is the strongest predictor of adjuvant systemic chemotherapy success. In patients with MAI < 3 (31% of all patients), ASCT does not improve survival.
Cytokeratin Profiles Identify Diagnostic Signatures in Colorectal Cancer Using Multiplex Analysis of Tissue Microarrays
Authors: Knösel Thomas , Emde Valeska , Schlüns Karsten , Schlag Peter Michael , Dietel Manfred , Petersen Iver
Published: January 2021

Background and aims: Recent cDNA expression profiling analyses indicate that within specific organ cancers Cytokeratins (CKs) dysregulation may identify subgroups with distinct biological phenotypes. Our objectives in this study were (1) to test whether cytokeratins were also distinct on the protein level, (2) to evaluate these biomarkers in a series of well‐characterised CRCs, (3) to apply hierarchical cluster analysis to immunohistochemical data. Methods: Tissue microarrays (TMA) comprising 468 CRC specimens from 203 patients were constructed to evaluate CK5, CK7, CK8, CK13, CK14, CK16, CK17, CK18, CK19 and CK20. In total, 2919 samples were analyzed. Results: Unsupervised hierarchical clustering discovered subgroups represented by reduced CK8 and CK20 expression, that differed by a shorter patients survival. The evaluation of the specific biomarkers by Kaplan–Meier analysis showed that reduced CK8 expression (p < 0.01) was significantly associated with shorter patients’ survival, but was not an independent factor correlated with tumour stage (pT), grading (G) and nodal stage (pN). Conclusions: Reduced coexpression of CK8 and CK20 may indicate an epithelial‐mesenchymal transition (EMT) representing an important step in the development of more aggressive CRCs. In addition, multiplex analysis of TMAs together with immunohistochemistry (IHC) supplemented by hierarchical clustering are a useful, promising and very powerful tool for the identification of tumour subgroups with diagnostic and prognostic signatures.
KRAS, p53 and BRAF Gene Mutations and Aneuploidy in Sporadic Colorectal Cancer Progression
Authors: Calistri Daniele , Rengucci Claudia , Seymour Ian , Leonardi Elena , Truini Mauro , Malacarne Davide , Castagnola Patrizio , Giaretti Walter
Published: January 2021

Background: The origin and mechanisms of chromosomal instability are still widely unknown. We previously investigated a limited number of human sporadic colorectal cancers (CRCs) and observed a statistically different occurrence of KRAS and p53 mutations among predetermined subgroups of tumors with different degrees of DNA aneuploidy. The aim of the present study was to further verify these observations by including BRAF gene analysis and by investigating a larger series of cases subdivided into Dukes′ stages A to D to reconstruct some form of chronological modulation for events during CRC progression. Methods: KRAS, p53, BRAF mutations and flow cytometric DNA Index were evaluated by established techniques in a series of 135 human sporadic CRCs. Results: p53, KRAS and BRAF mutations were found in 39%, 34%, and 4% of tumors, respectively. The frequency of p53 mutations increased from 15% for stage A to 48% for stage D and was highest in near‐diploid (DI 1.6) tumors. A similar correlation between gene mutations and DI values was observed for KRAS. The simultaneous presence of KRAS and p53 mutations was observed in only 11% of cases. Moreover, the co‐occurrence of p53 and KRAS mutations was only observed in near‐diploid and high‐aneuploid tumors. Conclusion: Our findings suggest that KRAS and p53 gene mutations, which are rarely simultaneous and are associated with specific DI aneuploid values, do not represent a synergistic evolutionary pathway but may influence mechanisms of chromosomal instability.
Distinct Chromosomal Profiles in Metastasizing and Non‐Metastasizing Colorectal Carcinomas
Authors: Ghadimi B. Michael , Grade Marian , Mönkemeyer Carsten , Kulle Bettina , Gaedcke Jochen , Gunawan Bastian , Langer Claus , Liersch Torsten , Becker Heinz
Published: January 2021

Background: The prognosis of colorectal cancer patients is to a considerable extent determined by the metastatic potency of the primary tumor. However, despite the fact that liver metastases are the leading cause of death for cancer patients, the molecular basis still remains poorly understood and independent prognostic markers have not been established. Materials and methods: Comparative genomic hybridization (CGH) was used to screen colorectal carcinomas without distant metastases (n=18) and carcinomas synchronously metastatic to the liver (n=18). We aimed to detect distinct chromosomal aberrations indicating a metastatic phenotype. Results and discussion: Metastatic tumors exhibited a significantly (P=0.03) higher ANCA value (13.8) if compared with non‐metastatic cancers (10.0). Furthermore, we observed that losses of chromosomal regions 1p32‐ter and 9q33‐ter were present at much higher frequencies in metastatic than in non‐metastatic cancers, respectively (P=0.02 and 0.04). Conclusion: These data indicate that metastatic tumors may be separated from non‐metastatic colorectal cancers based on their genomic profile.
Detection of Tumor Cells in Bone Marrow, Peripheral Blood and Lymph Nodes by Automated Imaging Devices
Authors: Mesker Wilma E. , Vrolijk Hans , Sloos Willem C. R. , Tollenaar Rob A. E. M. , Tanke Hans J.
Published: January 2021

The presence of tumor cells in bone marrow, peripheral blood and lymph nodes has proven its clinical and prognostic value. Since the frequency of these cells in bone marrow and blood is sometimes as low as 1 per million and due to the fact that for the analysis of lymph nodes many sectioning levels have to be analyzed, automated imaging devices have been suggested as an useful alternative to conventional manual screening of specimens. The aim of this paper is to review the performance of current equipment that is commercially available, based on literature published so far. Requirements for introducing this equipment for routine clinical practice are discussed.
Mixed Gastric Carcinomas Show Similar Chromosomal Aberrations in Both their Diffuse and Glandular Components
Authors: Carvalho Beatriz , Buffart Tineke E. , Reis Rui M. , Mons Thomas , Moutinho Cátia , Silva Paula , van Grieken Nicole C. T. , Grabsch Heike , van de Velde Cornelis J. H. , Ylstra Bauke , Meijer Gerrit A. , Carneiro Fátima
Published: January 2021

Gastric cancer is one of the most frequent malignancies in the world. Nonetheless, the knowledge of the molecular events involved in the development of gastric carcinoma is far from complete. One of the hallmarks of gastric cancer is chromosomal instability resulting in abnormal DNA copy number changes throughout the genome. Mixed gastric carcinomas constitute a rare histological entity, containing the two main histological phenotypes (diffuse and intestinal). Very little is known about the underlying mechanisms of phenotypic divergence in these mixed tumours. To the best of our knowledge only E‐Cadherin mutations were implicated so far in the divergence of these tumours and nothing is known about the involvement of chromosome copy number changes in the two divergent histological components. In this study, we compared the DNA copy number changes, in the two different components (diffuse and intestinal) of mixed gastric carcinomas by microarray – comparative genomic hybridisation (array CGH). The analysis of 12 mixed gastric carcinomas showed no significant differences in array CGH profiles between the diffuse and intestinal components of mixed carcinomas. This supports the idea that the phenotypic divergence within mixed gastric carcinomas is not caused by DNA chromosomal aberrations.
The CT‐Element of The C‐Myc Gene Does Not Predispose to Chromosomal Breakpoints in Burkitt′S Lymphoma
Authors: Weber Achim , Gutierrez Marina I. , Levens David
Published: January 2021

Background: Chromosomal translocations are causally related to the development of many tumors. In Burkitt′s lymphoma, abnormalities involving the c‐myc gene are essential. The CT‐element of the c‐myc promoter adopts non‐B‐conformation in vivo and in vitro, and therefore provides a potential fragile site. Methods: We have developed a LM‐PCR‐based approach to test if chromosomal breakpoints indeed cluster in this region. Results: Amplifying both, wild‐type as well as the translocated c‐myc gene by LM‐PCR, it was shown that chromosomal breakpoints did not cluster within the CT‐element. Conclusions: Therefore, the CT‐element is not especially susceptible to the formation of breakpoints leading to chromosomal translocations in Burkitt′s lymphoma.
Promoter Methylation Precedes Chromosomal Alterations in Colorectal Cancer Development
Authors: Derks Sarah , Postma Cindy , Moerkerk Peter T. M. , van den Bosch Sandra M. , Carvalho Beatriz , Hermsen Mario A. J. A. , Giaretti Walter , Herman James G. , Weijenberg Matty P. , de Bruïne Adriaan P. , Meijer Gerrit A. , van Engeland Manon
Published: January 2021

Background: Colorectal cancers are characterized by genetic and epigenetic alterations. This study aimed to explore the timing of promoter methylation and relationship with mutations and chromosomal alterations in colorectal carcinogenesis. Methods: In a series of 47 nonprogressed adenomas, 41 progressed adenomas (malignant polyps), 38 colorectal carcinomas and 18 paired normal tissues, we evaluated promoter methylation status of hMLH1, O6MGMT, APC, p14ARF, p16INK4A, RASSF1A, GATA-4, GATA-5, and CHFR using methylation‐specific PCR. Mutation status of TP53, APC and KRAS were studied by p53 immunohistochemistry and sequencing of the APC and KRAS mutation cluster regions. Chromosomal alterations were evaluated by comparative genomic hybridization. Results: Our data demonstrate that nonprogressed adenomas, progressed adenomas and carcinomas show similar frequencies of promoter methylation for the majority of the genes. Normal tissues showed significantly lower frequencies of promoter methylation of APC, p16INK4A, GATA-4, and GATA-5 (P‐values: 0.02, 0.02, 1.1×10−5 and 0.008 respectively). P53 immunopositivity and chromosomal abnormalities occur predominantly in carcinomas (P values: 1.1×10−5 and 4.1×10−10). Conclusions: Since promoter methylation was already present in nonprogressed adenomas without chromosomal alterations, we conclude that promoter methylation can be regarded as an early event preceding TP53 mutation and chromosomal abnormalities in colorectal cancer development.
Hepatitis C Virus Core Protein Transforms Murine Fibroblasts by Promoting Genomic Instability
Authors: Smirnova Irina S. , Aksenov Nikolai D. , Kashuba Elena V. , Payakurel Pawan , Grabovetsky Vadim V. , Zaberezhny Alexei D. , Vonsky Maxim S. , Buchinska Lubov , Biberfeld Peter , Hinkula Jorma , Isaguliants Maria G.
Published: January 2021

The oncogenic potential of hepatitis C virus (HCV) core protein has been demonstrated, but the precise mechanism of cell transformation triggered by HCV core is still unclear. This study shows that constitutive expression of HCV core protein (core) in NIH 3T3 murine fibroblasts triggers malignant transformation. At the preneoplastic stage, clones that expressed HCV core constitutively demonstrated genomic instability seen as disruption of the mitotic spindle cell checkpoint leading to increased ploidy. Transformation was completed by the loss of DNA and resistance to apoptosis induced by serum starvation. Simultaneously, cells acquired a capacity for anchorage independent growth and absence of contact inhibition. Inoculation of these transformed cells into severe combined immune deficiency (SCID) mice led to formation of solid core‐expressing tumors. Transformation and tumorigenicity of core‐expressing cell lines coincided with a 5‐ to 10‐fold repression of endogenous p53 transactivation. Thus, long‐term HCV core expression alone is sufficient for complete transformation of immortal fibroblasts that can then induce tumors in a susceptible host. This data suggests that malignant transformation by HCV core may occur through primary stress, induction of genomic instability, and further HCV core‐induced rescue of surviving mutated cells.