bluuebunny/crossref_metadata_2025 huggingface dataset:
Telomere-Associated Changes in Nuclear Architecture of Cancer-Associated Macrophage-like Cells in Liquid Biopsies from Melanoma Patients
Authors: Rangel-Pozzo Aline , Wechsler Janine , Groult Jessica , Da Meda Laetitia , Lebbe Celeste , Mai Sabine
Published: September 2022

During phagocytosis, tumor-associated macrophages (TAMs) can incorporate genetic material from tumor cells. The incorporation of extra genetic material may be responsible for advanced malignant behavior observed in some TAMs, making TAMs potentially important players in cancer progression. More recently, similar cells were described in the blood as cancer-associated macrophage-like cells (CAMLs). CAMLs may be equivalent to TAMs cells in the blood, and they express macrophage markers. However, their origin is still unclear. In a previous study, we showed for the first time the distinct telomere 3D structure of circulating tumor cells (CTCs) in melanoma and other cancers. In the present pilot study, we investigated, comparatively, the 3D telomere structure of CAMLs, CTCs and leucocytes from nine melanoma patients with metastatic cutaneous melanoma stage IV. CTC capture was performed by size-based filtration followed by cytological and immunocytological evaluation. Three-dimensional Quantitative Fluorescent in situ Hybridization was performed to measure differences in five 3D telomere parameters. Telomere parameters, such as number, length, telomere aggregates, nuclear volume, and a/c ratio, were compared among different cellular types (CTCs, CAMLs, and normal leucocytes). Three telomere parameters were significantly different between CAMLs and leucocytes. The combination of two telomere parameters (telomere length against the number of telomeres) resulted in the identification of two CAMLs subpopulations with different levels of genomic instability. Those populations were classified as profile 1 and 2. Profile 2, characterized by a high number of short telomeres, was observed in four of the nine melanoma patients. To our knowledge, this is the first pilot study to investigate 3D telomere parameters as hallmarks of nuclear architecture in CAMLs’ population in comparison to leucocytes from the same patient. Further studies involving a larger patient sample size are necessary to validate these findings and explore their potential prognostic value.
Hereditary Transthyretin-Related Amyloidosis: Genetic Heterogeneity and Early Personalized Gene Therapy
Authors: Dugo Ketty , Bruno Francesca , Sturiale Valentina , Brancato Desiree , Saccone Salvatore , Federico Concetta
Published: September 2022

Point mutations of the transthyretin (TTR) gene are related with hereditary amyloidosis (hATTR). The number of people affected by this rare disease is only partially estimated. The real impact of somatic mosaicism and other genetic factors on expressivity, complexity, progression, and transmission of the disease should be better investigated. The relevance of this rare disease is increasing and many efforts have been made to improve the time to diagnosis and to estimate the real number of cases in endemic and non-endemic areas. In this context, somatic mosaicism should be better investigated to explain the complexity of the heterogeneity of the hATTR clinical features, to better estimate the number of new cases, and to focus on early and personalized gene therapy. Gene therapy can potentially improve the living conditions of affected individuals and is one of the central goals in research on amyloidosis related to the TTR gene, with the advantage of overcoming liver transplantation as the sole treatment for hATTR disease.
Latent Tuberculosis: A Promising New Compound to Treat Non-Replicating and Intramacrophagic Mycobacteria
Authors: Campos Débora Leite , Demarqui Fernanda Manaia , Solcia Mariana Cristina , de Souza Paula Carolina , da Silva Maia Pedro Ivo , Deflon Victor Marcelo , Pavan Fernando Rogério
Published: September 2022

As a biologic reservoir of Mycobacterium tuberculosis (M. tb), one-quarter of the world population is infected with the well-known latent tuberculosis (LTBI). About 5–10% of LTBI patients will progress to active disease in the first years after primary infection and, despite using the recommended treatment, 20% can still reactivate the infection. A new LTBI treatment could minimize adverse effects and antibiotic resistance that can occur when the same drug is used to treat the latent and active disease. New hydrazones were evaluated, and they showed great inhibitory activity against intramacrophagic and non-replicating M. tb, commonly found at this stage of infection, in addition to bactericidal and narrow-spectrum activity. When tested against eukaryotic cells, the hydrazones showed great safety at different exposure times. In vitro, these compounds performed better than isoniazid and could be considered new candidates for LTBI treatment, which may promote greater engagement in its prescription and adherence.
Dielectrophoresis: An Approach to Increase Sensitivity, Reduce Response Time and to Suppress Nonspecific Binding in Biosensors?
Authors: Henriksson Anders , Neubauer Peter , Birkholz Mario
Published: September 2022

The performance of receptor-based biosensors is often limited by either diffusion of the analyte causing unreasonable long assay times or a lack of specificity limiting the sensitivity due to the noise of nonspecific binding. Alternating current (AC) electrokinetics and its effect on biosensing is an increasing field of research dedicated to address this issue and can improve mass transfer of the analyte by electrothermal effects, electroosmosis, or dielectrophoresis (DEP). Accordingly, several works have shown improved sensitivity and lowered assay times by order of magnitude thanks to the improved mass transfer with these techniques. To realize high sensitivity in real samples with realistic sample matrix avoiding nonspecific binding is critical and the improved mass transfer should ideally be specific to the target analyte. In this paper we cover recent approaches to combine biosensors with DEP, which is the AC kinetic approach with the highest selectivity. We conclude that while associated with many challenges, for several applications the approach could be beneficial, especially if more work is dedicated to minimizing nonspecific bindings, for which DEP offers interesting perspectives.
Effects of Acupuncture-Related Therapies in the Rehabilitation of Patients with Post-Stroke Aphasia—A Network Meta-Analysis of Randomized Controlled Trials
Authors: Liang Pengpeng , Li Yufei , Feng Yanan , Yin Guoliang , Chen Suwen , Liu Xiangyi , Zhang Fengxia
Published: September 2022

Objective: The purpose of this study was to evaluate the rehabilitation effects of four common interventions (BA: body acupuncture, SA: scalp acupuncture, TA: tongue acupuncture, SLT: speech and language training) used singly or in combination with language function in patients with post-stroke aphasia (PSA). Design: We systematically searched PubMed, EMBASE, Cochrane Library, Ovid, Web of Science, CNKI, VIP, and Wanfang from inception to 4 April 2022. Only randomized controlled trials that met the eligibility criteria were included. The risk of bias of studies included was assessed using the RoB-2 tool. The effects of different interventions for PSA patients were analyzed and ranked according to the surface under the cumulative ranking (SUCRA) analysis. Results: A total of 69 RCTs were included, including 5097 total participants. According to the results of the SUCRA curves, TA ranked highest in improving overall efficacy (SUCRA = 86%) and oral expression score (SUCRA = 86%). BA + TA ranked highest in increasing the comprehension score (SUCRA = 74.9%). BA + SA ranked highest in improving aphasia patients’ repetition (SUCRA = 89.2%) and denomination scores (SUCRA = 93%). Conclusions: Results of our network meta-analysis and SUCRA ranking showed that tongue acupuncture, body acupuncture + tongue acupuncture, and body acupuncture + scalp acupuncture seem to offer better advantages than other interventions for improving the language function in PSA patients. Moreover, it is noteworthy that our results are limited to the Chinese population, since all eligible studies are from China. Future well-designed studies with larger sample sizes and more ethnic groups are required to further verify these findings.
Signal Variability and Cognitive Function in Older Long-Term Survivors of Breast Cancer with Exposure to Chemotherapy: A Prospective Longitudinal Resting-State fMRI Study
Authors: Chen Bihong T. , Chen Zikuan , Deng Frank , Patel Sunita K. , Sedrak Mina S. , Root James C. , Ahles Tim A. , Razavi Marianne , Kim Heeyoung , Sun Can-Lan , Dale William
Published: September 2022

The purpose of this study was to assess the effect of chemotherapy on brain functional resting-state signal variability and cognitive function in older long-term survivors of breast cancer. This prospective longitudinal study enrolled women age ≥ 65 years of age who were breast cancer survivors after exposure to chemotherapy (CH), age-matched survivors not exposed to chemotherapy, and healthy controls. Participants completed resting-state functional brain MRI and neurocognitive testing upon enrollment (timepoint 1, TP1) and again two years later (timepoint 2, TP2). There were 20 participants in each of the three groups at TP1. The CH group showed a significant decrease in SDBOLD (blood-oxygen-level-dependent signal variability in standard deviation) in the right middle occipital gyrus (ΔSDBOLD = −0.0018, p = 0.0085, q (pFDR) = 0.043 at MNI (42, −76, 17)) and right middle temporal gyrus (ΔSDBOLD = −0.0021, p = 0.0006, q (pFDR) = 0.001 at MNI (63, −39, −12)). There were negative correlations between the crystallized composite scores and SDBOLD values at the right inferior occipital gyrus (correlation coefficient r = −0.84, p = 0.001, q (pFDR) = 0.016) and right middle temporal gyrus (r = −0.88, p = 0.000, q (pFDR) = 0.017) for the CH group at TP1. SDBOLD could be a potentially useful neuroimaging marker for older long-term survivors of breast cancer with exposure to chemotherapy.
Risk Factors of Transient Neurological Deficits and Perioperative Stroke after Revascularization in Patients with Moyamoya Disease
Authors: Zhang Xincheng , Yang Yiping , Gan Chao , He Xuejun , Liu Yanchao , Huang Yimin , Ma Xiaopeng , Wang Sheng , Shu Kai , Lei Ting , Zhang Huaqiu
Published: September 2022

Objective: To analyze the risk factors of transient neurological deficits (TND) and perioperative stroke in patients with MMD after extracranial–intracranial revascularization. Methods: A retrospective analysis of the clinical data of 183 patients with MMD undergoing 203 EC–IC bypass operation procedures from January 2018 to August 2020. According to whether TND and stroke occurred within 14 days after operation, univariate analysis and multivariate logistic regression were used. Results: TND occurred in 26 cases (12.8%) of revascularization. The results of the univariate analysis showed that history of diabetes, multiple episodes of preoperative symptoms, lesions involving the posterior circulation, and high postoperative blood pressure are the risk factors of TND. Further multivariate logistic regression analysis showed that multiple episodes of preoperative symptoms (p = 0.016) and lesions involving the posterior circulation (p = 0.014) are the independent risk factors for TND. Perioperative stroke occurred in 12 cases (5.9%). The results of the univariate analysis showed that older age, history of hypertension, preoperative cerebral infarction as the main symptom, lesions involving the posterior circulation, and high perioperative blood pressure are the risk factors of perioperative stroke. The results of multivariate logistic regression analysis showed that preoperative cerebral infarction as the main symptom (p = 0.015) is an independent risk factor for perioperative stroke. The occurrence of perioperative complications was not related to the improvement of follow-up mRS (Modified Rankin Scale) score and long-term cerebral rehemorrhage. Conclusions: Clinically, patients with MMD have multiple episodes of preoperative symptoms, lesions involving the posterior circulation, and preoperative cerebral infarction and should be attached when undergoing revascularization.
Sucrose Preference Test as a Measure of Anhedonic Behavior in a Chronic Unpredictable Mild Stress Model of Depression: Outstanding Issues
Authors: Markov Dmitrii D.
Published: September 2022

Despite numerous studies on the neurobiology of depression, the etiological and pathophysiological mechanisms of this disorder remain poorly understood. A large number of animal models and tests to evaluate depressive-like behavior have been developed. Chronic unpredictable mild stress (CUMS) is the most common and frequently used model of depression, and the sucrose preference test (SPT) is one of the most common tests for assessing anhedonia. However, not all laboratories can reproduce the main effects of CUMS, especially when this refers to a decrease in sucrose preference. It is also unknown how the state of anhedonia, assessed by the SPT, relates to the state of anhedonia in patients with depression. We analyzed the literature available in the PubMed database using keywords relevant to the topic of this narrative review. We hypothesize that the poor reproducibility of the CUMS model may be due to differences in sucrose consumption, which may be influenced by such factors as differences in sucrose preference concentration threshold, water and food deprivation, and differences in animals’ susceptibility to stress. We also believe that comparisons between animal and human states of anhedonia should be made with caution because there are many inconsistencies between the two, including in assessment methods. We also tried to offer some recommendations that should improve the reproducibility of the CUMS model and provide a framework for future research.
Effects of Anti-Seizure Medication on Sleep Spindles and Slow Waves in Drug-Resistant Epilepsy
Authors: Roebber Jennifer K. , Lewis Penelope A. , Crunelli Vincenzo , Navarrete Miguel , Hamandi Khalid
Published: September 2022

There is a close bidirectional relationship between sleep and epilepsy. Anti-seizure medications (ASM) act to reduce seizure frequency but can also impact sleep; this remains a relatively unexplored field given the importance of sleep on seizure occurrence, memory consolidation, and quality of life. We compared the effect of poly-ASM treatment on a night of sleep compared to an unmedicated night in patients with drug-resistant epilepsy, where ASMs were withdrawn and later restored as part of their pre-surgical evaluation. Within-subject analysis between medicated and unmedicated nights showed ASMs increased spindle (11–16 Hz) power and decreased slow wave (0.1–2 Hz) amplitude. Spindles became less strongly coupled to slow waves in the ASM night compared to no-ASM night, with effects to both the phase and strength of coupling and correlated with slow wave reduction. These effects were not seen in age-matched controls from the same unit where ASMs were not changed between two nights. Overall, we found that ASM polytherapy not only changed specific sleep waveforms, but also the fine interplay of spindle/slow wave coupling. Since these sleep oscillations impact both seizure occurrence and memory consolidation, our findings provide evidence towards a decoupling impact of ASMs on sleep that should be considered in future studies of sleep and memory disruption in people with epilepsy.
Gamma-Band Modulation in Parietal Area as the Electroencephalographic Signature for Performance in Auditory–Verbal Working Memory: An Exploratory Pilot Study in Hearing and Unilateral Cochlear Implant Children
Authors: Inguscio Bianca Maria Serena , Cartocci Giulia , Sciaraffa Nicolina , Nicastri Maria , Giallini Ilaria , Greco Antonio , Babiloni Fabio , Mancini Patrizia
Published: September 2022

This pilot study investigates the neurophysiological patterns of visual and auditory verbal working memory (VWM) in unilateral cochlear implant users (UCIs). We compared the task-related electroencephalogram (EEG) power spectral density of 7- to 13-year-old UCIs (n = 7) with a hearing control group (HC, n = 10) during the execution of a three-level n-back task with auditory and visual verbal (letters) stimuli. Performances improved as memory load decreased regardless of sensory modality (SM) and group factors. Theta EEG activation over the frontal area was proportionally influenced by task level; the left hemisphere (LH) showed greater activation in the gamma band, suggesting lateralization of VWM function regardless of SM. However, HCs showed stronger activation patterns in the LH than UCIs regardless of SM and in the parietal area (PA) during the most challenging audio condition. Linear regressions for gamma activation in the PA suggest the presence of a pattern-supporting auditory VWM only in HCs. Our findings seem to recognize gamma activation in the PA as the signature of effective auditory VWM. These results, although preliminary, highlight this EEG pattern as a possible cause of the variability found in VWM outcomes in deaf children, opening up new possibilities for interdisciplinary research and rehabilitation intervention.
Semantic Web Technologies for Indoor Environmental Quality: A Review and Ontology Design
Authors: Donkers Alex , Yang Dujuan , de Vries Bauke , Baken Nico
Published: September 2022

Indoor environmental quality (IEQ) affects occupants’ satisfaction, health, productivity, comfort, and well-being. IoT developments enable better monitoring of IEQ parameters; however, integrating the various types of heterogeneous data from both the IoT and BIM domains is cumbersome and capital intensive, and therefore, limits the potential of smart buildings. Semantic web technologies can reduce heterogeneity issues, which is necessary to facilitate complex IEQ models. An ontology integrating data related to a building’s topology and its static and dynamic properties is still lacking. The outline of this research is twofold. First, a systematic literature review was conducted to find state-of-the-art semantic web technologies related to building topology, static properties, and dynamic properties from the IoT and BIM domains. By graphically reviewing various ontologies, their valuable patterns, commonalities, and best practices were revealed. Secondly, those results were used to develop a new ontology that integrates topological building information with static and dynamic properties. This Building Performance Ontology (BOP) provides a generic upper-level description of properties and two lower-level ontologies representing observations and actuation. The ontology results in intuitive queries and is both horizontally and vertically extensible. Multiple levels of detail are introduced to ensure practical applicability and efficient patterns based on the data modeler’s needs. BOP opens up a new range of research opportunities in the IEQ domain.
Integrating Virtual Reality and Building Information Modeling for Improving Highway Tunnel Emergency Response Training
Authors: Yu Xinhua , Yu Pengfei , Wan Chao , Wang Di , Shi Weixiang , Shou Wenchi , Wang Jun , Wang Xiangyu
Published: September 2022

During the last two decades, managers have been applying Building Information Modeling (BIM) to improve the quality of management as well as operation. The effectiveness of applications within a BIM environment is restrained by the limited immersive experience in virtual environments. Defined as the immersive visualization of virtual scenes, Virtual Reality (VR) is an emerging technology that can be actively explored to expand BIM to more usage. This paper highlights the need for a structured methodology for the integration of BIM/VR and gives a generic review of BIM and VR in training platforms for management in infrastructures. The rationales for fire evacuation training were formed based on the review. Then, methods of configuring BIM + VR prototypes were formulated for emergency response in highway tunnels. Furthermore, a conceptual framework integrating BIM with VR was proposed to enable the visualization of the physical context in real-time during the training. The result indicated that, extended to the training system of highway management via the “hand” of BIM, the VR solution can benefit more areas, such as the cost of fire evacuation drills in highway tunnels and the tendency of accidents to occur in the emergency response.
Numerical Study Regarding the Seismic Response of a Moment-Resisting (MR) Reinforced Concrete (RC) Frame Structure with Reduced Cross-Sections of the RC Slabs
Authors: Sococol Ion , Mihai Petru , Petrescu Tudor-Cristian , Nedeff Florin , Nedeff Valentin , Agop Maricel , Luca Bogdan-Ionel
Published: September 2022

In the first part of the current study, the effectiveness of the transversal cross-section reduction method for RC beams in marginal areas (by means of mechanical drilling) was validated. The said method “encourages” the formation of plastic hinges at the beam ends and, at the same time, allows for taking into account the bending stiffness of RC slabs, which is exerted upon the RC beams. In these conditions, the second part of the current research study (i.e., the current manuscript) highlights the real mode of reducing the lateral stiffness of the slabs upon the RC beams. These elements form a common body, together with the beam–column frame node. The same method as in the first part of the study—“weakening” the plates in the corner area through vertical drilling, without affecting the integrity of the reinforcing elements—was used. The analytical MR RC frame model, studied by means of the comparative method, highlights the efficiency of the transversal cross-section reduction method for RC slabs. Basically, the directing of the plastic deformations from the weakened slab areas towards the marginal areas of the reinforced concrete beams takes place. The beams rotate as far as the weakened slab areas allow its plastic deformation, thus being possible to observe the partial conservation effect of the beam–column frame joint. Furthermore, for the analytical model with the maximum number of vertical holes in the corner areas of the concrete plate, minimal plastic deformations are recorded for the marginal areas of the concrete columns. A partial conservation of the formation mechanism of the “beam-slab-frame node” common rigid block is also noted. Consequently, the dissipation of the seismic energy is made in a partially controlled and directed manner, in the “desired” areas, according to the “Strong Columns—Weak Beams” (SCWB) ductile mechanism of the lateral behavior to seismic actions for reinforced concrete frame structures. The mechanism is specified in current design norms for RC frame systems. The effectiveness of the method for reducing the transversal section of the RC plates in the corner areas by means of transversal drilling is highlighted and validated from the perspective of the local and global ductile seismic response of reinforced concrete frame structures. A significant reduction in the bending stiffness of the slabs upon the beams and a real development of the plastic hinges in the marginal areas of the beams (together with partial implications and plastic deformations) were observed.
Population-Based Assessment of Determining Predictors for Discharge Disposition in Patients with Bladder Cancer Undergoing Radical Cystectomy
Authors: Kumar Raj A. , Asanad Kian , Miranda Gus , Cai Jie , Djaladat Hooman , Ghodoussipour Saum , Desai Mihir M. , Gill Inderbir S. , Cacciamani Giovanni E.
Published: September 2022

Objective: To assess predictors of discharge disposition—either home or to a CRF—after undergoing RC for bladder cancer in the United States. Methods: In this retrospective, cohort study, patients were divided into two cohorts: those discharged home and those discharged to CRF. We examined patient, surgical, and hospital characteristics. Multivariable logistic regression models were used to control for selected variables. All statistical tests were two-sided. Patients were derived from the Premier Healthcare Database. International classification of disease (ICD)-9 (<2014), ICD-10 (≥2015), and Current Procedural Terminology (CPT) codes were used to identify patient diagnoses and encounters. The population consisted of 138,151 patients who underwent RC for bladder cancer between 1 January 2000 and 31 December 2019. Results: Of 138,151 patients, 24,922 (18.0%) were admitted to CRFs. Multivariate analysis revealed that older age, single/widowed marital status, female gender, increased Charlson Comorbidity Index, Medicaid, and Medicare insurance are associated with CRF discharge. Rural hospital location, self-pay status, increased annual surgeon case, and robotic surgical approach are associated with home discharge. Conclusions: Several specific patient, surgical, and facility characteristics were identified that may significantly impact discharge disposition after RC for bladder cancer.
Targeted Depletion of Hyaluronic Acid Mitigates Murine Breast Cancer Growth
Authors: Zamloot Vic , Ebelt Nancy Danielle , Soo Catherine , Jinka Shweta , Manuel Edwin R.
Published: September 2022

Hyaluronic acid (HA) is highly elevated in breast cancers compared to normal breast tissue and is associated with increased tumor aggressiveness and poor prognosis. HA interacts with cell-trafficking CD44 receptors to promote tumor cell migration and proliferation and regulates both pro- and anti-inflammatory cytokine production through tumor-associated macrophages. The highly negative charge of HA enables its uptake of vast amounts of water that greatly increases the tumor interstitial fluidic pressure, which, combined with the presence of other extracellular matrix components such as collagen, results in tumor stroma with abnormal vasculature, hypoxia, and increased drug resistance. Thus, the degradation of HA in breast cancer may attenuate growth and improve permeability to anticancer agents. Previous methods to deplete tumor HA have resulted in significant off-tumor effects due to the systemic use of mammalian hyaluronidases. To overcome this, we developed a hyaluronidase-secreting Salmonella typhimurium (YS-HAse) that specifically and preferentially colonizes tumors to deplete HA. We show that the systemic administration of YS-HAse in immunocompetent murine models of breast cancer enhances tumor perfusion, controls tumor growth, and restructures the tumor immune contexture. These studies highlight the utility of YS-HAse as a novel microbial-based therapeutic that may also be combined with existing therapeutic approaches.
Low Expression of RGS2 Promotes Poor Prognosis in High-Grade Serous Ovarian Cancer
Authors: Ihlow Jana , Monjé Nanna , Hoffmann Inga , Bischoff Philip , Sinn Bruno Valentin , Schmitt Wolfgang Daniel , Kunze Catarina Alisa , Darb-Esfahani Sylvia , Kulbe Hagen , Braicu Elena Ioana , Sehouli Jalid , Denkert Carsten , Horst David , Taube Eliane Tabea
Published: September 2022

RGS2 regulates G-protein signaling by accelerating hydrolysis of GTP and has been identified as a potentially druggable target in carcinomas. Since the prognosis of patients with high-grade serous ovarian carcinoma (HGSOC) remains utterly poor, new therapeutic options are urgently needed. Previous in vitro studies have linked RGS2 suppression to chemoresistance in HGSOC, but in situ data are still missing. In this study, we characterized the expression of RGS2 and its relation to prognosis in HGSOC on the protein level by immunohistochemistry in 519 patients treated at Charité, on the mRNA level in 299 cases from TCGA and on the single-cell level in 19 cases from publicly available datasets. We found that RGS2 is barely detectable on the mRNA level in both bulk tissue (median 8.2. normalized mRNA reads) and single-cell data (median 0 normalized counts), but variably present on the protein level (median 34.5% positive tumor cells, moderate/strong expression in approximately 50% of samples). Interestingly, low expression of RGS2 had a negative impact on overall survival (p = 0.037) and progression-free survival (p = 0.058) on the protein level in lower FIGO stages and in the absence of residual tumor burden. A similar trend was detected on the mRNA level. Our results indicated a significant prognostic impact of RGS2 protein suppression in HGSOC. Due to diverging expression patterns of RGS2 on mRNA and protein levels, posttranslational modification of RGS2 is likely. Our findings warrant further research to unravel the functional role of RGS2 in HGSOC, especially in the light of new drug discovery.
Altered Plasma, Urine, and Tissue Profiles of Sulfatides and Sphingomyelins in Patients with Renal Cell Carcinoma
Authors: Jirásko Robert , Idkowiak Jakub , Wolrab Denise , Kvasnička Aleš , Friedecký David , Polański Krzysztof , Študentová Hana , Študent Vladimír , Melichar Bohuslav , Holčapek Michal
Published: September 2022

Purpose: RCC, the most common type of kidney cancer, is associated with high mortality. A non-invasive diagnostic test remains unavailable due to the lack of RCC-specific biomarkers in body fluids. We have previously described a significantly altered profile of sulfatides in RCC tumor tissues, motivating us to investigate whether these alterations are reflected in collectible body fluids and whether they can enable RCC detection. Methods: We collected and further analyzed 143 plasma, 100 urine, and 154 tissue samples from 155 kidney cancer patients, together with 207 plasma and 70 urine samples from 214 healthy controls. Results: For the first time, we show elevated concentrations of lactosylsulfatides and decreased levels of sulfatides with hydroxylated fatty acyls in body fluids of RCC patients compared to controls. These alterations are emphasized in patients with the advanced tumor stage. Classification models are able to distinguish between controls and patients with RCC. In the case of all plasma samples, the AUC for the testing set was 0.903 (0.844–0.954), while for urine samples it was 0.867 (0.763–0.953). The models are able to efficiently detect patients with early- and late-stage RCC based on plasma samples as well. The test set sensitivities were 80.6% and 90%, and AUC values were 0.899 (0.832–0.952) and 0.981 (0.956–0.998), respectively. Conclusion: Similar trends in body fluids and tissues indicate that RCC influences lipid metabolism, and highlight the potential of the studied lipids for minimally-invasive cancer detection, including patients with early tumor stages, as demonstrated by the predictive ability of the applied classification models.
The Drivers, Mechanisms, and Consequences of Genome Instability in HPV-Driven Cancers
Authors: Porter Vanessa L. , Marra Marco A.
Published: September 2022

Human papillomavirus (HPV) is the causative driver of cervical cancer and a contributing risk factor of head and neck cancer and several anogenital cancers. HPV’s ability to induce genome instability contributes to its oncogenicity. HPV genes can induce genome instability in several ways, including modulating the cell cycle to favour proliferation, interacting with DNA damage repair pathways to bring high-fidelity repair pathways to viral episomes and away from the host genome, inducing DNA-damaging oxidative stress, and altering the length of telomeres. In addition, the presence of a chronic viral infection can lead to immune responses that also cause genome instability of the infected tissue. The HPV genome can become integrated into the host genome during HPV-induced tumorigenesis. Viral integration requires double-stranded breaks on the DNA; therefore, regions around the integration event are prone to structural alterations and themselves are targets of genome instability. In this review, we present the mechanisms by which HPV-dependent and -independent genome instability is initiated and maintained in HPV-driven cancers, both across the genome and at regions of HPV integration.
The Clonal Diversity of Peripheral B Cell Receptor Immune Repertoire Impaired by Residual Malignant B Cells Predicts Treatment Efficacy in B Cell Lymphoma Patients
Authors: Wu Meng , Zhang Jing , Wang Yi , Mi Lan , Wang Xiaopei , Liu Weiping , Fu Jie , Song Haifeng , Song Yuqin , Zhu Jun
Published: September 2022

Germinal center (GC) is the vital locus for the evolution of naïve B cells into memory B and plasma cells, but also a hotbed for the proliferation of malignant B cells. We hypothesized that malignant B cells may locally or globally impact GCs to produce peripheral B cell receptor immune repertoire (BCR IR) with reduced clonal diversity. In this study, we first validated our hypothesis in a novel human in-vitro GC (hiGC) model. The addition of the diffuse large B cell lymphoma (DLBCL) cells to the hiGC culture attenuated the rate of diversity growth. For clinical validation, we collected samples from 17 DLBCL patients at various points during high-dose therapy and autologous stem cell rescue. The elimination and reestablishment of the patients’ lymphatic pool allowed us to unambiguously monitor the impact of tumor cells on the replenishment of the peripheral BCR IR. Compared to the nine patients who did not relapse after treatment, relapsed patients tended to have a slower rate of recovery regarding the clonal diversity of their peripheral BCR IR. Our results suggest a mechanistic and clinical connection between residual tumor cells and abnormal peripheral BCR IR, which may corelate with treatment efficacy in B cell lymphomas.
Treatment of Pineal Region Rosette-Forming Glioneuronal Tumors (RGNT)
Authors: Michel Anna , Dinger Thiemo Florin , Jabbarli Ramazan , Dammann Philipp , Uerschels Anne-Kathrin , Oppong Marvin Darkwah , Özkan Neriman , Junker Andreas , Sure Ulrich , Wrede Karsten Henning
Published: September 2022

Background: Rosette-forming glioneuronal tumor (RGNT) is an extremely rare entity described for the first time in the WHO classification of tumors of the central nervous system in 2007. Predominantly, single case reports of RGNT in the pineal region have been published, and specific therapy concepts are pending. Methods: The study group comprised all patients with the RGNT (CNS WHO grade 1) in the pineal region that underwent microsurgical tumor removal in our center (August 2018–June 2021). Surgical strategy, histological findings, and clinical outcome are presented, and the results are evaluated and compared to published case reports. Results: Four male patients aged under 50 years (range between 20 and 48 years) and one female patient, 51 years old, were included in this study. Chronic headaches and generalized epileptic seizures were the main symptoms. Supra-cerebellar infratentorial gross total tumor resection (GTR) was performed in two cases, two patients underwent subtotal tumor resection, and an endoscopic biopsy was performed in case five. Conclusion: In cases where surgical resection seems feasible with a reasonable surgical risk, we advocate GTR. Regular and long-term MRI follow-up is essential to detect a slow tumor progression. The role of additional chemotherapy or radiotherapy remains unclear.
TREM2 Is Associated with Advanced Stages and Inferior Prognosis in Oral Squamous Cell Carcinoma
Authors: Struckmeier Ann-Kristin , Radermacher Anne , Fehrenz Michael , Alansary Dalia , Wartenberg Philipp , Wagner Mathias , Scheller Anja , Hess Jochen , Moratin Julius , Freudlsperger Christian , Hoffmann Jürgen , Thurner Lorenz , Roemer Klaus , Freier Kolja , Horn Dominik
Published: September 2022

Triggering receptor expressed on myeloid cells 2 (TREM2) is suggested to hamper antitumor immune response in multiple cancers. However, the role of TREM2 in oral squamous cell carcinoma (OSCC) and its expression in tumor-associated macrophages (TAMs) are unknown. In this study, TREM2 expression was analyzed in the primary tumors and corresponding lymph-node metastases of OSCC patients via immunohistochemistry on tissue microarrays. Human peripheral blood mononuclear cells (PBMCs) and single-cell suspensions of tumor and healthy adjacent tissues were analyzed for the presence of TREM2+ macrophages and TAMs using flow cytometry. The serum levels of soluble TREM2 (sTREM2) were quantified using an enzyme-linked immunosorbent assay. High TREM2 expression was associated with advanced UICC stages (Spearman’s rank correlation (SRC), p = 0.04) and significantly reduced survival rates in primary tumors (multivariate Cox regression, progression-free survival: hazard ratio (HR) of 2.548, 95% confidence interval (CI) of 1.089–5.964, p = 0.028; overall survival: HR of 2.17, 95% CI of 1.021–4.613, p = 0.044). TREM2 expression was significantly increased in the PBMCs of OSCC patients in UICC stage IV compared with healthy controls (ANOVA, p < 0.05). The serum levels of sTREM2 were higher in advanced UICC stages, but they narrowly missed significance (SRC, p = 0.059). We demonstrated that TREM2 was multi-factorially associated with advanced stages and inferior prognosis in OSCC patients and that it could serve as a prognostic biomarker in OSCC patients. Targeting TREM2 has the potential to reshape the local and systemic immune landscape for the potential enhancement of patients’ prognosis.
Implementing Risk-Stratified Breast Screening in England: An Agenda Setting Meeting
Authors: McWilliams Lorna , Evans D. Gareth , Payne Katherine , Harrison Fiona , Howell Anthony , Howell Sacha J. , French David P. ,   on behalf of the Breast Screening Risk-Stratification Agenda Setting Group
Published: September 2022

It is now possible to accurately assess breast cancer risk at routine NHS Breast Screening Programme (NHSBSP) appointments, provide risk feedback and offer risk management strategies to women at higher risk. These strategies include National Institute for Health and Care Excellence (NICE) approved additional breast screening and risk-reducing medication. However, the NHSBSP invites nearly all women three-yearly, regardless of risk. In March 2022, a one-day agenda setting meeting took place in Manchester to discuss the feasibility and desirability of implementation of risk-stratified screening in the NHSBSP. Fifty-eight individuals participated (38 face-to-face, 20 virtual) with relevant expertise from academic, clinical and/or policy-making perspectives. Key findings were presented from the PROCAS2 NIHR programme grant regarding feasibility of risk-stratified screening in the NHSBSP. Participants discussed key uncertainties in seven groups, followed by a plenary session. Discussions were audio-recorded and thematically analysed to produce descriptive themes. Five themes were developed: (i) risk and health economic modelling; (ii) health inequalities and communication with women; (iii); extending screening intervals for low-risk women; (iv) integration with existing NHSBSP; and (v) potential new service models. Most attendees expected some form of risk-stratified breast screening to be implemented in England and collectively identified key issues to be resolved to facilitate this.
Primary Treatment Results in Patients with Ovarian, Fallopian or Peritoneal Cancer—Results of a Clinical Cancer Registry Database Analysis in Germany
Authors: Armbrust Robert , Ledwon Peter , Von Rüsten Anne , Schneider Constanze , Sehouli Jalid
Published: September 2022

Background: The current therapy of ovarian cancer is based on the so-called “Three-Pillar-Model”, consisting of surgery, chemotherapy and maintenance therapy. This study represents the first major analysis of a federal cancer database of OC patients from the states Berlin/Brandenburg in Germany. The primary objective was to evaluate the prevailing established quality indicators surgical outcome, adjuvant chemotherapy and integrity of surgical staging in early stages. Methods: Data from the Clinical Cancer Registry for Brandenburg and Berlin of the years 2009–2019 were analyzed. Objectives were defined by a working group of selected physicians. Descriptive statistics were performed, as well as survival analysis. Results: A total of 2771 primary OC cases were included. Results regarding histological subtype met the suspected allocation with predominantly high-grade serous OC in advanced stage. The rate of complete surgical staging in FIGO stages I–IIA was 57%, and the rate of macroscopic complete resection in >FIGO III was 53%. Five-year survival rate varied from 79% (FIGO I) to 40% (FIGO III). Rate of adjuvant chemotherapy was above 50%. Conclusion: The results elucidate quality measurements and treatment results and show good treatment outcomes in patients with primary diagnosis. However, they also indicate deficits and can help to establish new quality indicators to further improve the treatment.
Radiation Recall Pneumonitis: A Rare Syndrome That Should Be Recognized
Authors: Jan Pei-Rung , Chang John Wen-Cheng , Wu Chiao-En
Published: September 2022

Radiation recall pneumonitis (RRP) is a rare but severe condition which has been mainly detected in the previously irradiated lung of patients with cancer after administering inciting agents, most commonly antineoplastic regimens including chemotherapy, targeted therapy, or immunotherapy. More recently, coronavirus disease vaccines were found to induce RRP. In addition to typical radiation pneumonitis (RP) or drug-induced interstitial lung disease, the management of RRP requires withholding inciting agents and steroid therapy. Thus, the occurrence of RRP could significantly impact cancer treatment, given that inciting agents are withheld temporarily and even discontinued permanently. In the present review, we discuss the current understanding and evidence on RRP and provide additional insights into this rare but severe disease.
Concomitant Use of Sulforaphane Enhances Antitumor Efficacy of Sunitinib in Renal Cell Carcinoma In Vitro
Authors: Tsaur Igor , Thomas Anita , Taskiran Emine , Rutz Jochen , Chun Felix K.-H. , Haferkamp Axel , Juengel Eva , Blaheta Roman A.
Published: September 2022

Chronic treatment of renal cell carcinoma (RCC) with the tyrosine kinase inhibitor sunitinib (ST) inevitably induces resistance and tumor re-activation. This study investigated whether adding the natural compound sulforaphane (SFN) with its anti-cancer properties could improve ST efficacy in vitro. The RCC cell lines A498, Caki1, KTCTL26, and 786O were exposed to ST, SFN, or both (dual therapy, DT) before (short-term exposure) and during ST-resistance buildup (long-term 8-week exposure). Tumor growth, proliferation, and clone formation were evaluated, as was cell cycle progression and cell cycle regulating proteins. In nonresistant cells (short-term), DT induced a higher reduction in cell viability in three cell lines as compared to monotherapy with either ST or SFN. Long-term SFN or DT significantly reduced tumor growth and proliferation, whereas ST alone had no effect or even elevated proliferation in three cell lines. SFN or DT (but not ST alone) also blocked clonogenic growth. Both long-term SFN and DT enhanced the number of cells in the S- and/or G2/M-phase. Protein analysis in 786O cells revealed a down-regulation of cyclin dependent kinase (CDK) 1 and 2. CDK2 or Cyclin A knockdown caused reduced 786O growth activity. SFN therefore inhibits or delays resistance to chronic ST treatment.
CXCR6+ Tumor-Associated Macrophages Identify Immunosuppressive Colon Cancer Patients with Poor Prognosis but Favorable Response to Adjuvant Chemotherapy
Authors: Chang Jiang , Lin Songbin , Mao Yihao , Xu Yuqiu , Zhang Zhiyuan , Wu Qi , Chen Yijiao , Wei Ye , Feng Qingyang , Xu Jianmin
Published: September 2022

We explored the infiltration and prognostic value of CXCR6+TAMs in all stages of colon cancer (CC) patients and assessed predictive ability as a biomarker for different ACT regimens among high-risk stage II and stage III patients in both primary and validation cohorts. Two independent cohorts of 360 and 126 consecutive colon cancer patients were enrolled from two medical centers of Zhongshan Hospital. Immunofluorescence and immunohistochemistry were performed to detect the density of CXCR6+TAMs and activated CD8+ T cells. The infiltration of CXCR6+TAMs was higher in tumor tissues and increased with advanced tumor stage. A high density of CXCR6+TAMs predicted worse overall survival (OS) in all CC patients (HR = 2.49, 95% CI = (1.68, 3.70), p < 0.001), and was an independent risk factor verified by Cox regression analysis (HR = 1.68, 95% CI = (1.09, 2.59), p = 0.019). For high-risk stage II and stage III patients with a high density of CXCR6+TAMs, better disease-free survival (DFS) (HR = 0.32, 95% CI = (0.11, 0.89), p = 0.003), and OS (HR = 0.28, 95% CI = (0.07, 1.11), p = 0.014) were observed in the 6-month treatment group. There was a negative relationship between the density of CXCR6+TAMs and CD8+ T cells (R = −0.51, p < 0.001) as well as activated CD8+ T cells (R = −0.54, p < 0.001). Higher levels of IL-6 and lower levels of IL-2R and TNF-α were expressed in high-CXCR6+ TAM-density patients, which indicates that CXCR6+TAMs contribute to an immunosuppressive microenvironment. CXCR6+TAMs predicted prognosis and response to different durations of ACT in CC patients. CXCR6+TAMs were associated with an immunosuppressive microenvironment and suppressed the activation of CD8+ T cells.
The Histone Demethylase HR Suppresses Breast Cancer Development through Enhanced CELF2 Tumor Suppressor Activity
Authors: Shen Yao , Singh Jasvinder , Sah Bindeshwar , Chen Zhongming , Ha Wootae , Henzler Christine , Su Tao , Xie Lillian , Deng Yibin , Li Gen , Guo Hua , Hibshoosh Hanina , Liu Liang
Published: September 2022

The hairless (HR) gene encodes a transcription factor with histone demethylase activity that is essential for development and tissue homeostasis. Previous studies suggest that mutational inactivation of HR promotes tumorigenesis. To investigate HR mutations in breast cancer, we performed targeted next-generation sequencing using DNA isolated from primary breast cancer tissues. We identified HR somatic mutations in approximately 15% of the patient cohort (n = 85), compared with 23% for BRCA2, 13% for GATA3, 7% for BRCA1, and 3% for PTEN in the same patient cohort. We also found an average 23% HR copy number loss in breast cancers. In support of HR’s antitumor functions, HR reconstitution in HR-deficient human breast cancer cells significantly suppressed tumor growth in orthotopic xenograft mouse models. We further demonstrated that HR’s antitumor activity was at least partly mediated by transcriptional activation of CELF2, a tumor suppressor with RNA-binding activity. Consistent with HR’s histone demethylase activity, pharmacologic inhibition of histone methylation suppressed HR-deficient breast cancer cell proliferation, migration and tumor growth. Taken together, we identified HR as a novel tumor suppressor that is frequently mutated in breast cancer. We also showed that pharmacologic inhibition of histone methylation is effective in suppressing HR-deficient breast tumor growth and progression.
Targeting JWA for Cancer Therapy: Functions, Mechanisms and Drug Discovery
Authors: Ding Kun , Liu Xia , Wang Luman , Zou Lu , Jiang Xuqian , Li Aiping , Zhou Jianwei
Published: September 2022

Tumor heterogeneity limits the precision treatment of targeted drugs. It is important to find new tumor targets. JWA, also known as ADP ribosylation factor-like GTPase 6 interacting protein 5 (ARL6IP5, GenBank: AF070523, 1998), is a microtubule-associated protein and an environmental response gene. Substantial evidence shows that JWA is low expressed in a variety of malignancies and is correlated with overall survival. As a tumor suppressor, JWA inhibits tumor progression by suppressing multiple oncogenes or activating tumor suppressor genes. Low levels of JWA expression in tumors have been reported to be associated with multiple aspects of cancer progression, including angiogenesis, proliferation, apoptosis, metastasis, and chemotherapy resistance. In this review, we will discuss the structure and biological functions of JWA in tumors, examine the potential therapeutic strategies for targeting JWA and explore the directions for future investigation.