bluuebunny/crossref_metadata_2025 huggingface dataset:
Study on protective measures against diseases of almonds caused by fungi: A case study in Tashkent region of Uzbekistan
Authors: Yuldosheva D , Khujaev O , Gulmurodov R , Gulmurodova Sh
Published: December 2021

Among the fruit trees, almond has a special place and is an ancient and traditional type of fruit crop for many countries of the world. Leading research centers around the world have conducted research to study the prevalence, development, damage, and control measures of the almond tree fungi Stigmina carpophila and Monilinia cinerea, which cause widespread perforated spot and moniliosis burns. As a result, it was possible to preserve the almond crop lost under the influence of these diseases. Even today, research aimed at developing effective measures to control the fungal diseases of the almond tree remains relevant.
Assimilation dynamics of saline soil areas by cultivating biomeliorant herbal plant in the lower Amudarya region
Authors: Jumaniyazov J , Tukhtayev B , Abdullaev I , Khudayberganov N , Iskandarov A
Published: December 2021

5 types of herbal plants (Herbal Chamomile, Herbal Clove, Dyed Royan, Peppermint, Liquorice) were developed for growth and development, productivity and primary agro-technics of their cultivation in the saline soils of Khorezm region. Bio-ecological and bio-melioration properties of salt-tolerant herbal plants as assimilators in the process of assimilation of saline soils were studied. The adaptor-genetic potential of the selected herbal plants as a plant that assimilates in moderately and strongly saline soils was determined. The agrochemical properties of the soil and its mechanism have been developed in the process of bio-melioration carried out using the cultivation of assimilating herbal plants.
Dark-eyed females: sexually dimorphic prespawning coloration results from sex-specific physiological response to hormone exposure in the sand gobyPomatoschistus minutus(Gobiiformes: Gobiidae)
Authors: Olsson Karin H , Nilsson Sköld Helen , Merilaita Sami , Kvarnemo Charlotta
Published: December 2021

The function and regulation of female nuptial colour signals are poorly understood. In fish, colour is often mediated by chromatophores, allowing for rapid and versatile signalling. Here, we examine a distinct but temporary black line around the eyes and snout (‘dark eyes’) displayed by female sand gobies before spawning and never observed in males. We investigate the regulatory mechanism of the display by analysing the number of melanophores in both sexes in vitro and their response to hormonal exposure. We also test the hypothesis that dark eyes serve an anti-glare function and focus the line of sight, by analysing the frequency, intensity and duration of the display in bright and dim light, with and without males present. We show that the sexes do not differ in terms of the number of melanophores, but that males and females respond in different ways to exposure to melanocyte-stimulating hormone, which has a stronger dilatory effect in females and results in a darker line. However, the darkness of the iris is not affected. Neither light levels nor the presence of potential mates affect the frequency of the dark eye display, but the display is longer lasting and more intense in the presence of smaller nest-holding males.
Separating and reintegrating latent variables to improve classification of genomic data
Authors: Payne Nora Yujia , Gagnon-Bartsch Johann A
Published: December 2021

Genomic data sets contain the effects of various unobserved biological variables in addition to the variable of primary interest. These latent variables often affect a large number of features (e.g., genes), giving rise to dense latent variation. This latent variation presents both challenges and opportunities for classification. While some of these latent variables may be partially correlated with the phenotype of interest and thus helpful, others may be uncorrelated and merely contribute additional noise. Moreover, whether potentially helpful or not, these latent variables may obscure weaker effects that impact only a small number of features but more directly capture the signal of primary interest. To address these challenges, we propose the cross-residualization classifier (CRC). Through an adjustment and ensemble procedure, the CRC estimates and residualizes out the latent variation, trains a classifier on the residuals, and then reintegrates the latent variation in a final ensemble classifier. Thus, the latent variables are accounted for without discarding any potentially predictive information. We apply the method to simulated data and a variety of genomic data sets from multiple platforms. In general, we find that the CRC performs well relative to existing classifiers and sometimes offers substantial gains.
A timeframe for mint evolution: towards a better understanding of trait evolution and historical biogeography in Lamiaceae
Authors: Rose Jeffrey P , Xiang Chun-Lei , Sytsma Kenneth J , Drew Bryan T
Published: December 2021

Lamiaceae are one of the largest and most economically important families of flowering plants. Despite focused study on relationships within subclades, higher-level relationships have been under-studied. Moreover, the herbaceous habit of much of the family has resulted in a poor fossil record and has hampered estimates of divergence times. Using a new dataset of five plastid loci from 178 members of Lamiaceae representing all subfamilies and nearly all tribes, we clarify major infrafamilial relationships and present a robust set of divergence times. We use this phylogenetic hypothesis as a platform to test previous hypotheses regarding the historical biogeography and evolution of major traits in the family. We confirm the placement of subfamily Nepetoideae, show continued uncertainty in the placement of subfamilies Ajugoideae and Premnoideae and highlight extreme discordance with recent results from nuclear data. Lamiaceae originated during the Late Cretaceous as woody plants with nutlet fruits and four stamens, probably in South-East Asia. Most subfamilies diverged during the Eocene, perhaps facilitated by climatic cooling. Our results provide a valuable set of secondary dates for Lamiaceae and highlight the need for focused study of subfamilies Callicarpoideae and Viticoideae. Our results also provide several hypotheses regarding trait or range-dependent diversification.
Modulation of the oral glucocorticoid system during black raspberry mediated oral cancer chemoprevention
Authors: Nedungadi Divya , Ryan Nathan , Anderson Kelvin , Lamenza Felipe F , Jordanides Pete P , Swingler Michael J , Rakotondraibe Liva , Riedl Kenneth M , Iwenofu Hans , Oghumu Steve
Published: December 2021

Recent reports suggest that glucocorticoids (GCs), which can be synthesized in the oral mucosa, play an important role in cancer development. Therefore, the objectives of this study were to characterize the role of the oral GC system in oral cancer, and determine the effect of black raspberry (BRB) administration on GC modulation during oral cancer chemoprevention. We determined the expression of GC enzymes in various oral cancer cell lines, and investigated the role of the GC inactivating enzyme HSD11B2 on CAL27 oral cancer cells using siRNA mediated knockdown approaches. Using two in vivo models of oral carcinogenesis with 4-nitroquinoline 1-oxide carcinogen on C57Bl/6 mice and F344 rats, we determined the effect of BRB on GC modulation during head and neck squamous cell carcinoma chemoprevention. Our results demonstrate that HSD11B2, which inactivates cortisol to cortisone, is downregulated during oral carcinogenesis in clinical and experimental models. Knockdown of HSD11B2 in oral cancer cells promotes cellular proliferation, invasion and expression of angiogenic biomarkers EGFR and VEGFA. An ethanol extract of BRB increased HSD11B2 expression on oral cancer cells. Dietary administration of 5% BRB increased Hsd11b2 gene and protein expression and reduced the active GC, corticosterone, in cancer-induced mouse tongues. Our results demonstrate that the oral GC system is modulated during oral carcinogenesis, and BRB administration upregulates Hsd11b2 during oral cancer chemoprevention. In conclusion, our findings challenge the use of synthetic GCs in head and neck cancer, and support the use of natural product alternatives that potentially modulate GC metabolism in a manner that supports oral cancer chemoprevention.
Outcomes of decreasing versus increasing cardiac troponin in patients admitted with non-ST-segment elevation myocardial infarction: the Atherosclerosis Risk in Communities Surveillance Study
Authors: Arora Sameer , Cavender Matthew A , Chang Patricia P , Qamar Arman , Rosamond Wayne D , Hall Michael E , Rossi Joseph S , Kaul Prashant , Caughey Melissa C
Published: December 2021

Background

The fourth universal definition of myocardial infarction requires an increase or decrease in cardiac troponin for the classification of non-ST-segment elevation myocardial infarction. We sought to determine whether the characteristics, management, and outcomes of patients admitted with non-ST-segment elevation myocardial infarction differ by the initial biomarker pattern.

Methods

We identified patients in the Atherosclerosis Risk in Communities Surveillance Study admitted with chest pain and an initially elevated cardiac troponin I, who presented within 12 hours of symptom onset and were classified with non-ST-segment elevation myocardial infarction. A change in cardiac troponin I required an absolute difference of at least 0.02 ng/mL on the first day of hospitalization, prior to invasive cardiac procedures.

Results

A total of 1926 hospitalizations met the inclusion criteria, with increasing cardiac troponin I more commonly observed (78%). Patients with decreasing cardiac troponin I were more often black (45% vs. 35%) and women (54% vs. 40%), and were less likely to receive non-aspirin antiplatelets (44% vs. 63%), lipid-lowering agents (62% vs. 80%), and invasive angiography (38% vs. 64%). Inhospital mortality was 3%, irrespective of the cardiac troponin I pattern. However, patients with decreasing cardiac troponin I had twice the 28-day mortality (12% vs. 5%; P=0.01). Fatalities within 28 days were more often attributable to non-cardiovascular causes in those with decreasing versus increasing cardiac troponin I (75% vs. 38%; P=0.01).

Conclusion

Patients presenting with chest pain and an initially elevated cardiac troponin I which subsequently decreases are less often managed by evidence-based therapies and have greater mortality, primarily driven by non-cardiovascular causes. Whether associations are attributable to type 2 myocardial infarction or a subacute presentation merits further investigation.
Diverse Effects of Mass Media on Concerns about Immigration: New Evidence from Germany, 2001–2016
Authors: Erhard Lukas , Heiberger Raphael H , Windzio Michael
Published: December 2021

Media discourse is often seen as an important condition of people’s attitudes and perceptions. Despite a rich literature, however, it is not well understood how media exposure influences attitudes towards immigrants. In contrast to previous studies, we argue that people rely on ‘availability heuristics’ shaped by mass media. From that point of view, it is the specific content of media discourse on immigration that affects people’s concerns. We use structural topic models to classify media content of more than 24,000 articles of leading German newspapers from 2001 to 2016. Utilizing linear fixed-effects models allows us to relate a person’s concern towards immigration, as reported in the German Socioeconomic Panel, to prevalent topics discussed in print media while controlling for several confounding factors (e.g., party preferences, interest in politics, etc.). We find a robust relationship between topic salience and attitudes towards integration. Our results reveal that specific topics with negative contents (e.g., domestic violence) increase concerns, while others (e.g., scientific studies, soccer) decrease concerns substantially, underlining the importance of available information provided by media. In addition, people with higher education are generally less affected by media salience of topics.
Individualized or fixed approach to pulmonary vein isolation utilizing the fourth-generation cryoballoon in patients with paroxysmal atrial fibrillation: the randomized INDI-FREEZE trial
Authors: Heeger Christian Hendrik , Popescu Sorin Stefan , Saraei Roza , Kirstein Bettina , Hatahet Sascha , Samara Omar , Traub Anna , Fehe Marcel , D’Ambrosio Gabriele , Keelani Ahmad , Schlüter Michael , Eitel Charlotte , Vogler Julia , Kuck Karl Heinz , Tilz Roland Richard
Published: December 2021

Aims

Cryoballoon (CB) based pulmonary vein isolation (PVI) is a widely used technique for treatment of atrial fibrillation (AF); however the ideal energy dosing has not yet been standardized. This was a single-centre randomized clinical trial aiming at assessing the safety, acute efficacy, and clinical outcome of an individualized vs. a fixed CB ablation protocol using the fourth-generation CB (CB4) guided by pulmonary vein (PV) potential recordings and CB temperature.

Methods and results

Patients were randomized in a 1:1 fashion to two different dosing protocols: INDI-FREEZE group (individualized protocol): freeze-cycle duration of time to effect plus 90 s or interruption of the freeze-cycle and repositioning CB if a CB temperature of −30°C was not within 40 s. Control group (fixed protocol): freeze-cycle duration of 180 s. No-bonus freeze-cycle was applied in either patient group. The primary endpoint was freedom from atrial tachyarrhythmia at 12 months. Secondary end points included procedural parameters and complications. A total of 100 patients with paroxysmal AF were prospectively enrolled. No difference was seen in the primary endpoint [INDI-FREEZE group: 38/47 (81%) vs. control group: 40/47, (85%), P = 0.583]. The total freezing time was significantly shorter in the INDI-FREEZE group (157 ± 56 s vs. 212 ± 83 s, P < 0.001), while procedure duration (57.9 ± 17.9 min vs. 63.2 ± 20.2 min, P = 0.172) was similar. No differences were seen in the minimum CB and oesophageal temperatures as well as in periprocedural complications.

Conclusion

Compared to the fixed protocol, the individualized approach provides a similar safety profile and clinical outcome, while reducing the total freezing time.
The Association of Loneliness With Health and Social Care Utilization in Older Adults in the General Population: A Systematic Review
Authors: Smith Kimberley J , Victor Christina
Published: December 2021

Background and Objectives

Loneliness is proposed to be linked with increased service use. This review examined the association of loneliness and health and social care utilization (HSCU) in older adults from the general population.

Research Design and Methods

Four databases were screened for studies that examined the association of loneliness (predictor) with HSCU (outcome) in older adults (defined as the majority of sample 60 or older). Study quality was assessed with the National Institutes for Health scale for observational cohorts and cross-sectional studies.

Results

We identified 32 studies, of which 9 prospective studies were evaluated as being good or good–fair quality. Two good–fair quality studies found that loneliness at baseline was associated with subsequent admission to a residential care home. There was emerging evidence that loneliness was associated with emergency department use (n = 1) and cardiovascular disease-specific hospitalization (n = 1). Once adjusted for confounders, the highest quality studies found no association of baseline loneliness with physician utilization, outpatient service utilization, skilled nursing facility use, and planned or unplanned hospital admissions. The remaining studies were cross-sectional, or of fair to poor quality, and inadequate to reliably determine whether loneliness was associated with a subsequent change in HSCU.

Discussion and implications

There was heterogeneity in study design, measurement, and study quality. This generated an inconsistent evidence base where we cannot determine clear inferences about the relationship between loneliness and HSCU. Only one consistent finding was observed between 2 good–fair quality studies regarding care home admission. To determine clinical implications and make reliable inferences, additional good quality longitudinal research is needed.
Implementing COVID-19 surveillance through inter-organizational coordination: a qualitative study of three cities in Colombia
Authors: Turner Simon , Segura Carolina , Niño Natalia
Published: December 2021

Introducing comprehensive surveillance is recommended as an urgent public health measure to control and mitigate the spread of coronavirus disease 2019 (COVID-19) worldwide. However, its implementation has proven challenging as it requires inter-organizational coordination among multiple healthcare stakeholders. The purpose of this study was to examine the role of soft and hard mechanisms in the implementation of inter-organizational coordination strategies for COVID-19 surveillance within Colombia, drawing on evidence from the cities of Bogotá, Cali and Cartagena. The study used a case study approach to understand the perspectives of local and national authorities, insurance companies and health providers in the implementation of inter-organizational coordination strategies for COVID-19 surveillance. Eighty-one semi-structured interviews were conducted between June and November 2020. The data were analysed by codes and categorized using New NVivo software. The study identified inter-organizational coordination strategies that were implemented to provide COVID-19 surveillance in the three cities. Both soft (e.g. trust and shared purpose) and hard mechanisms (e.g. formal agreements and regulations) acted as mediators for collaboration and helped to address existing structural barriers in the provision of health services. The findings suggest that soft and hard mechanisms contributed to promoting change among healthcare system stakeholders and improved inter-organizational coordination for disease surveillance. The findings contribute to evidence regarding practices to improve coordinated surveillance of disease, including the roles of new forms of financing and contracting between insurers and public and private health service providers, logistics regarding early diagnosis in infectious disease and the provision of health services at the community level regardless of insurance affiliation. Our research provides evidence to improve disease surveillance frameworks in fragmented health systems contributing to public health planning and health system improvement.
Responses of benthic calcifying algae to ocean acidification differ between laboratory and field settings
Authors: Page Heather N , Bahr Keisha D , Cyronak Tyler , Jewett Elizabeth B , Johnson Maggie D , McCoy Sophie J
Published: December 2021

Accurately predicting the effects of ocean and coastal acidification on marine ecosystems requires understanding how responses scale from laboratory experiments to the natural world. Using benthic calcifying macroalgae as a model system, we performed a semi-quantitative synthesis to compare directional responses between laboratory experiments and field studies. Variability in ecological, spatial, and temporal scales across studies, and the disparity in the number of responses documented in laboratory and field settings, make direct comparisons difficult. Despite these differences, some responses, including community-level measurements, were consistent across laboratory and field studies. However, there were also mismatches in the directionality of many responses with more negative acidification impacts reported in laboratory experiments. Recommendations to improve our ability to scale responses include: (i) developing novel approaches to allow measurements of the same responses in laboratory and field settings, and (ii) researching understudied calcifying benthic macroalgal species and responses. Incorporating these guidelines into research programs will yield data more suitable for robust meta-analyses and will facilitate the development of ecosystem models that incorporate proper scaling of organismal responses to in situ acidification. This, in turn, will allow for more accurate predictions of future changes in ecosystem health and function in a rapidly changing natural climate.
Memory-phenotype CD4+ T cells: a naturally arising T lymphocyte population possessing innate immune function
Authors: Kawabe Takeshi , Sher Alan
Published: December 2021

In conventional adaptive immune responses, upon recognition of foreign antigens, naive CD4+ T lymphocytes are activated to differentiate into effector/memory cells. In addition, emerging evidence suggests that in the steady state, naive CD4+ T cells spontaneously proliferate in response to self-antigens to acquire a memory phenotype (MP) through homeostatic proliferation. This expansion is particularly profound in lymphopenic environments but also occurs in lymphoreplete, normal conditions. The ‘MP T lymphocytes’ generated in this manner are maintained by rapid proliferation in the periphery and they tonically differentiate into T-bet-expressing ‘MP1’ cells. Such MP1 CD4+ T lymphocytes can exert innate effector function, producing IFN-γ in response to IL-12 in the absence of antigen recognition, thereby contributing to host defense. In this review, we will discuss our current understanding of how MP T lymphocytes are generated and persist in steady-state conditions, their populational heterogeneity as well as the evidence for their effector function. We will also compare these properties with those of a similar population of innate memory cells previously identified in the CD8+ T lymphocyte lineage.
NDRG1 in Aggressive Breast Cancer Progression and Brain Metastasis
Authors: Villodre Emilly S , Hu Xiaoding , Eckhardt Bedrich L , Larson Richard , Huo Lei , Yoon Ester C , Gong Yun , Song Juhee , Liu Shuying , Ueno Naoto T , Krishnamurthy Savitri , Pusch Stefan , Tripathy Debu , Woodward Wendy A , Debeb Bisrat G
Published: December 2021

Background

N-Myc downstream regulated gene 1 (NDRG1) suppresses metastasis in many human malignancies, including breast cancer, yet has been associated with worse survival in patients with inflammatory breast cancer. The role of NDRG1 in the pathobiology of aggressive breast cancers remains elusive.

Methods

To study the role of NDRG1 in tumor growth and brain metastasis in vivo, we transplanted cells into cleared mammary fat pads or injected them in tail veins of SCID/Beige mice (n = 7-10 per group). NDRG1 protein expression in patient breast tumors (n = 216) was assessed by immunohistochemical staining. Kaplan-Meier method with 2-sided log-rank test was used to analyze the associations between NDRG1 and time-to-event outcomes. A multivariable Cox regression model was used to determine independent prognostic factors. All statistical tests were 2-sided.

Results

We generated new sublines that exhibited a distinct propensity to metastasize to the brain. NDRG1-high–expressing cells produced more prevalent brain metastases (100% vs 44.4% for NDRG1-low sublines, P = .01, Fisher’s exact test), greater tumor burden, and reduced survival in mice. In aggressive breast cancer cell lines, silencing NDRG1 led to reduced migration, invasion, and tumor-initiating cell subpopulations. In xenograft models, depleting NDRG1 inhibited primary tumor growth and brain metastasis. In patient breast tumors, NDRG1 was associated with aggressiveness: NDRG1-high expression was also associated with shorter overall survival (hazard ratio [HR] = 2.27, 95% confidence interval [95% CI] = 1.20 to 4.29, P = .009) and breast cancer–specific survival (HR = 2.19, 95% CI = 1.07 to 4.48, P = .03). Multivariable analysis showed NDRG1 to be an independent predictor of overall survival (HR = 2.17, 95% CI = 1.10 to 4.30, P = .03) and breast cancer–specific survival rates (HR = 2.27, 95% CI = 1.05 to 4.92, P = .04).

Conclusions

We demonstrated that NDRG1 drives tumor progression and brain metastasis in aggressive breast cancers and that NDRG1-high expression correlates with worse clinical outcomes, suggesting that NDRG1 may serve as a therapeutic target and prognostic biomarker in aggressive breast cancers.
The Survival Impact of Second Primary Lung Cancer in Patients With Lung Cancer
Authors: Choi Eunji , Luo Sophia J , Aredo Jacqueline V , Backhus Leah M , Wilkens Lynne R , Su Chloe C , Neal Joel W , Le Marchand Loïc , Cheng Iona , Wakelee Heather A , Han Summer S
Published: December 2021

Background

Lung cancer survivors have a high risk of developing second primary lung cancer (SPLC), but little is known about the survival impact of SPLC diagnosis.

Methods

We analyzed data from 138 969 patients in the Surveillance, Epidemiology, and End Results (SEER), who were surgically treated for initial primary lung cancer (IPLC) in 1988-2013. Each patient was followed from the date of IPLC diagnosis to SPLC diagnosis (for those with SPLC) and last vital status through 2016. We performed multivariable Cox regression to evaluate the association between overall survival and SPLC diagnosis as a time-varying predictor. To investigate potential effect modification, we tested interaction between SPLC and IPLC stage. Using data from the Multiethnic Cohort Study (MEC) (n = 1540 IPLC patients with surgery), we evaluated the survival impact of SPLC by smoking status. All statistical tests were 2-sided.

Results

A total of 12 115 (8.7%) patients developed SPLC in SEER over 700 421 person-years of follow-up. Compared with patients with single primary lung cancer, those with SPLC had statistically significantly reduced overall survival (hazard ratio [HR] = 2.12, 95% confidence interval [CI] = 2.06 to 2.17; P < .001). The effect of SPLC on reduced survival was more pronounced among patients with early stage IPLC vs advanced-stage IPLC (HR = 2.14, 95% CI = 2.08 to 2.20, vs HR = 1.43, 95% CI = 1.21 to 1.70, respectively; Pinteraction < .001). Analysis using MEC data showed that the effect of SPLC on reduced survival was statistically significantly larger among persons who actively smoked at initial diagnosis vs those who formerly or never smoked (HR = 2.31, 95% CI = 1.48 to 3.61, vs HR = 1.41, 95% CI = 0.98 to 2.03, respectively; Pinteraction = .04).

Conclusions

SPLC diagnosis is statistically significantly associated with decreased survival in SEER and MEC. Intensive surveillance targeting patients with early stage IPLC and active smoking at IPLC diagnosis may lead to a larger survival benefit.
Spatially resolved Lyman-α emission around radio bright quasars
Authors: Shukla Gitika , Srianand Raghunathan , Gupta Neeraj , Petitjean Patrick , Baker Andrew J , Krogager Jens-Kristian , Noterdaeme Pasquier
Published: December 2021

We use Southern African Large Telescope (SALT) to perform long-slit spectroscopic observations of 23 newly discovered radio-loud quasars (RLQs) at 2.7 < z < 3.3. The sample consists of powerful AGN brighter than 200 mJy at 1.4 GHz and is selected on the basis of mid-infrared colours i.e. unbiased to the presence of dust. We report seven confirmed and five tentative detections of diffuse Ly α emission in the sample. We present the properties of diffuse Ly α emission and discuss in detail its relationship to different quasar properties. We find strong dependence of Ly α halo detection rate on the extent of radio source, spectral luminosity of RLQ at 420 MHz (L420MHz), presence of associated C iv absorption and nuclear He ii emission line equivalent width. As seen in previous surveys, the full width at half-maximum of diffuse Ly α emission in the case of confirmed detections are much higher (i.e. >1000 km s−1 in all, except one). Using the samples of high-z radio-loud quasars and galaxies from literature, we confirm the correlation between the Ly α halo luminosity and its size with $L_{\rm 420\, \rm MHz}$. The same quantities are found to be correlating weakly with the projected linear size of the radio emission. Our sample is the second largest sample of RLQs being studied for the presence of diffuse Ly α emission and fills in a redshift gap between previous such studies. Integral field spectroscopy is required to fully understand the relationship between the large-scale radio emission and the overall distribution, kinematics, and overdensity of Ly α emission in the field of these RLQs.
DNA supercoiling-mediated collective behavior of co-transcribing RNA polymerases
Authors: Tripathi Shubham , Brahmachari Sumitabha , Onuchic José N , Levine Herbert
Published: December 2021

Multiple RNA polymerases (RNAPs) transcribing a gene have been known to exhibit collective group behavior, causing the transcription elongation rate to increase with the rate of transcription initiation. Such behavior has long been believed to be driven by a physical interaction or ‘push’ between closely spaced RNAPs. However, recent studies have posited that RNAPs separated by longer distances may cooperate by modifying the DNA segment under transcription. Here, we present a theoretical model incorporating the mechanical coupling between RNAP translocation and the DNA torsional response. Using stochastic simulations, we demonstrate DNA supercoiling-mediated long-range cooperation between co-transcribing RNAPs. We find that inhibiting transcription initiation can slow down the already recruited RNAPs, in agreement with recent experimental observations, and predict that the average transcription elongation rate varies non-monotonically with the rate of transcription initiation. We further show that while RNAPs transcribing neighboring genes oriented in tandem can cooperate, those transcribing genes in divergent or convergent orientations can act antagonistically, and that such behavior holds over a large range of intergenic separations. Our model makes testable predictions, revealing how the mechanical interplay between RNAPs and the DNA they transcribe can govern transcriptional dynamics.
SPDR-2 Histopathological investigation of the oligodendroglial tumors resected following alkylating agent chemotherapy
Authors: Masato Nakaya , Kanazawa Tokunori , Ohara Kentaro , Kitamura Yohei , Yoshida Kazunari , Sasaki Hikaru
Published: December 2021

Oligodendrogliomas, i.e., lower grade gliomas with 1p/19q codeletion, are often responsive to chemotherapy, however, those tumors eventually recur and life-limiting in the majority of patients despite initial chemotherapeutic response. We have been treating those patients with upfront chemotherapy and subsequent resection following tumor volume decrease since 2006. This study aimed to elucidate the histological changes and the mechanism of recurrence after alkylating agent chemotherapy in oligodendrogliomas. Fifteen oligodendrogliomas (Grade 2: 12, Grade 3: 3) resected following tumor volume decrease after alkylating agent chemotherapy were included and compared with their pre-chemotherapy specimens. Histological changes were investigated using hematoxylin-eosin staining, and changes in proliferative activity, status of glioma stem cells (GSCs), and tumor-infiltrating macrophages were assessed using immunohistochemistry. The frequent histological findings following chemotherapy included a sparse glial background, abundant foamy cell infiltration, gliosis, calcification, and nuclear degradation. The Ki-67/MIB-1 index decreased and the number of macrophages increased after chemotherapy. Moreover, the ratio of GSCs to total tumor cells increased after chemotherapy. GSCs and macrophages constitute the mechanism of resistance to and recurrence after alkylating agent chemotherapy in oligodendrogliomas.
ET-5 Biological effects of simultaneous use of multiple drugs in neutron capture therapy using rat brain tumor model
Authors: Kawabata Shinji , Kashiwagi Hideki , Yoshimura Kohei , Fukuo Yusuke , Hiramatsu Ryo , Nonoguchi Naosuke , Furuse Motomasa , Miyatake Shin-Ichi , Wanibuchi Masahiko
Published: December 2021

The world’s first clinical trial of boron neutron capture therapy (BNCT), which treats malignant brain tumors with a single dose of neutron irradiation using multiple boron drugs simultaneously, was performed at our institution, and its excellent results have stimulated BNCT research around the world. BNCT is a particle irradiation therapy that biologically targets cancer cells, and is expected to be a “new option for cancer treatment” because it can deliver a dose of radiation at the cellular level. In the case of BNCT using a combination of multiple drugs, a method to appropriately consider the biological effects of the combination in the dose calculation has not been established. At present, BNCT based on an accelerator-based irradiation system and a boron drug (BPA) based on essential amino acids has been approved by the regulatory approval for head and neck cancer and has shown good results in brain tumors. As basic research, we have continued to develop new boron drugs, which will be essential in the future, and have explored the interpretation of the biological effects of multiple boron drugs in combination and the optimal conditions required for drug development. The survival curve of BNCT in a rat brain tumor model showed that the effect of the new drug alone was comparable to that of BPA, and the effect of the combination was improved, but the effect of the combination did not match the prediction of the combined biological effect derived from each drug. However, it has been found that the effect of the combination does not match the prediction based on the combination of biological effects derived from each drug. In other words, even if the equivalent X-ray equivalent dose (Gy-Eq) is calculated, the combined effect of some drugs exceeds the prediction, while the combined effect of other drugs is poor.
TB-8 Genetic and molecular properties of long-term proliferating tumorsphere -forming glioma derived cells
Authors: Kijima Noriyuki , Kanematsu Daisuke , Shofuda Tomoko , Yoshioka Ema , Yamamoto Atsuyo , Handa Yukako , Fukusumi Hayato , Katsuma Asako , Sumida Miho , Moriuchi Shusuke , Nonaka Masahiro , Okita Yoshiko , Tsuyuguchi Naohiro , Uda Takehiro , Kawashima Toshiyuki , Fukai Junya , Kodama Yoshinori , Mano Masayuki , Higuchi Yuichiro , Suemizu Hiroshi , Kanemura Yonehiro
Published: December 2021

Long-term proliferating tumorsphere-forming glioma derived cells (LTP-TS-GDCs) and patient derived xenografts (PDXs) are essential tools for translational research for glioma. However, only small subsets of glioma samples are established as LTP-TS and/or PDXs and little is known about the genetics and molecular properties of LTP-TS -forming GDCs and PDX. In this study, we aim to analyze the characteristics of LTP-TS -forming GDCs and PDXs. We tried primary sphere cultures from 56 glioma patient-derived samples and established 11 LTP-TS-GDCs out of 45 glioblastoma samples and no long-term sphere culture was isolated from grade3 and grade 2 gliomas. LTP-TS-GDCs had self-renewal ability and possessed certain multipotency. However, they significantly less expressed SOX1 FOXG1 and TUBB3, whereas they expressed LGALS1 and EN1 significantly higher than normal neural stem/progenitor cells. In addition, we found that LTP-TS-GDCs shared the same genetic profiles with original patients’ tumors. Furthermore, we investigated the genetic differences between the glioma tissues which were successfully established as LTP-TS-GDCs and those which were not. We found that glioma tissues with TERT promotor mutations and triple copy number alteration (CNA) [EGFR, CDKN2A, and PTEN loci] are significantly established as LTP-TS-GDCs. Lastly, we next investigated in vivo characteristics of glioma PDXs. We have injected glioma PDXs lines into immunodeficient mice brains and histopathologically analyzed the characteristics of xenografts. Each xenograft well recapitulated histological features of original patients’ tumors and tumor cells remarkably invade through subventricular zone. In conclusion, each LTP-TS-GDCs and PDXs had various gene expression profiles, reflecting intratumoral and interpatient heterogeneities of glioma. In addition, TERT promotor mutations and triple CNA significantly correlated with success rate of LTP-TS-GDCs. These findings will be of use and advance the preclinical and translational researches of glioma.
IM-4 Impact of oHSV activated NOTCH signaling in tumor microenvironment and its impact on anti-tumor immunity
Authors: Yoshihiro Otani , Yoo Ji Young , Lawler Sean E , Chiocca Antonio E , Kaur Balveen
Published: December 2021

Oncolytic herpes simplex virus-1 (oHSV) is novel FDA-approved immunotherapy for advanced melanoma patients in US. Also, oHSV is recently approved for the treatment of recurrent GBM in Japan. We have shown that oHSV treatment of GBM cells induces NICD cleavage and NOTCH activation in adjacent uninfected glioma cells via HSV-1 microRNA-H16 (Otani Y and Yoo JY, Clin Cancer Res, 2020), however, the consequences of NOTCH on immunotherapy in GBM is unknow. Here we have investigated the impact of oHSV-induced NOTCH signaling on the tumor microenvironment (TME). Analysis of TCGA GBM data and experimental murine models revealed NOTCH induced immunosuppressive myeloid cell recruitment and limited anti-tumor immunity. In oHSV treated tissue, viral infection educated tumor associated macrophages to secrete CCL2 which recruited monocytic myeloid derived suppressor cell (MDSC) that attenuated anti-tumor immunity. Consistent with this, CCL2 induction was also observed in serum of recurrent GBM patients treated with oHSV (NCT03152318). Importantly, blockade of NOTCH signaling reduced the oHSV induced immunosuppressive environment and activated a CD8 dependent anti-tumor memory response. These findings present the opportunities for combination therapies that can help improve therapeutic benefit and anti-tumor immunity in GBM.
BOT-5 Chrysanthemum morifolium extract improves doxorubicin-induced cardiomyopathy by suppressing apoptosis in mouse heart
Authors: Ono Masaya , Mochizuki Saho , Tsuchitani Kanako , Iwashimizu Sonoka , Sunagawa Yoichi , Funamoto Masafumi , Shimizu Kana , Shimizu Satoshi , Katanasaka Yasufumi , Hasegawa Koji , Morimoto Tatsuya
Published: December 2021

Background: Doxorubicin is widely used for the treatment of various malignant tumors. However, doxorubicin causes cumulative and dose-dependent cardiotoxicity, ranging from occult changes in myocardial structure and function to severe cardiomyopathy and congestive heart failure. Since this problem affects the QOL and survival of cancer patients, solutions for this problem are urgently needed. Recently, it has been reported that Chrysanthemum morifolium extracts (CME) have antioxidant and anti-inflammatory activities. The purpose of this study is to clarify whether CME decreases doxorubicin-induced cardiotoxicity and prevents the development of heart failure. Methods and Results: H9C2 cardiomyoblast cells were treated with CME (0.3, 1 mg/mL) for 2 hours and then stimulated with doxorubicin. After 24 hours incubation, surviving cells were evaluated by MTT assay. CME dose-dependently decreased doxorubicin-induced cardiotoxicity in H9C2 cells. Western blotting showed that CME significantly suppressed doxorubicin-induced increases in four markers of apoptosis: p53, phosphorylated p53, and cleaved caspase-9 and -3. Next, to investigate the effects of CME on doxorubicin-induced cardiomyopathy in vivo, C57BL6 mice were orally administered with CME (400 mg/kg/day) or vehicle daily from 2 days before doxorubicin treatment and then treated once intraperitoneally with doxorubicin (20 mg/kg). The survival ratio of the CME-treated group was significantly higher than that of the vehicle-treated group. Echocardiographic analysis at 7 days after doxorubicin stimulation revealed that CME had significantly improved doxorubicin-induced left ventricular systolic dysfunction. Apoptotic cells in mouse heart tissue were detected by TUNEL assay, which showed that CME significantly suppressed doxorubicin-induced apoptosis. Discussion: These results indicate that CME decreases doxorubicin-induced cardiotoxicity both in vitro and in vivo, suggesting that CME might possess the therapeutic potency to reduce doxorubicin-induced cardiotoxicity in cancer patients. Further studies are required to assess the effectiveness of CME for preventing doxorubicin-induced heart failure in clinical settings.
ACT-6 Clinical manifestations of the patients with relapsed glioblastoma after bevacizumab treatment
Authors: Kikuchi Miyu , Takahashi Masamichi , Yanagisawa Syunsuke , Ono Makoto , Miyakita Yasuji , Tamura Yukie , Kawauchi Daisuke , Narita Yoshitaka
Published: December 2021

Introduction:The outcome of glioblastoma (GBM) is improving recently, but still only temozolomide and bevacizumab (BEV) are recognized as the effective agents that are reimbursed in Japan. On large clinical trials, BEV prolonged progression free survival (PFS) but the remaining survival period from the relapse after BEV is only 3–5 month. On this study, we retrospectively analyzed the data of GBM patients who were treated with BEV to explore the best usage of BEV.Methods:230 patients were diagnosed as GBM and received BEV from July 2013 to March 2021 in our institution. Among them, 104 patient, whose clinical courses were followed, were included in this study. (M:F=59:45, median age was 65.5) Results:The patients were divided into three groups by when they used BEV; upfront group at first line therapy, 1st relapse group at second line, and 2nd+ relapse group at more than third line. There were 42, 35, 27 patients in each group. The median overall survival (OS) was 17.6, 24.7, 46.1 month (p<0.0001), median PFS after BEV treatment (PFSpBEV) was 8.8, 5.1, 5.0 month (p=0.2532), and the median survival after BEV treatment (OSpBEV) was 15.0, 9.9, 9.2 month (p=0.4437), respectively. There were 64 patients (22, 25, 17 in each group) who reached progressive disease (PD) after BEV. The median survival after PD (OSpBEVpPD) was 4.5, 5.8, 4.3 month (p=0.1590), respectively.Discussion:At the first onset, we use BEV only when the patients have low PS. Our results showed that OS was significantly longer when BEV was used in the later stage, but there was no significant difference in OS or PFS after BEV treatment. Especially OSpBEVpPD was 4–6 month regardless of the timing of BEV. To improve the treatment outcome of GBM, breakthrough therapy is needed in addition to optimizing the usage of BEV.
PEDT-1 Integrated diagnoses of pediatric gliomas in our institute by cIMPACT-NOW recommendations
Authors: Yamamura Toshihiro , Tamura Kaoru , Kobayashi Daisuke , Inaji Motoki , Tanaka Yoji , Maehara Taketoshi
Published: December 2021

Purpose:Since many genetic abnormalities in glioma have been revealed in recent years, Integrated diagnoses are necessary in the updated fourth edition of the WHO Classification of Tumors of the Central Nervous System(CNS) published in 2016. The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) was established to provide a forum to evaluate and recommend proposed changes to future CNS tumor classification. We retrospectively classified pediatric gliomas in our hospital in accordance with cIMPACT-NOW recommendations. Methods: This study includes 13 consecutive glioma patients under the age of 18 who underwent surgical resection at our hospital from 2000 to 2021. Histopathological diagnoses and molecular status such as IDH, H3F3A and BRAF were analyzed. Results: There were four females and nine males, ranging in age from 0 to 17 years, median 9.0 years. Three pilocytic astrocytomas (PA) and a polymorphous low-grade neuroepithelial tumor of the young (PLNTY) had BRAF fusion. Four cases were classified as Diffuse midline glioma, H3K27M-altered. Two cases were classified as Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype. No genetic alteration was observed in two diffuse astrocytoma cases. An anaplastic oligodendroglioma case with PDGFRA amplification could not be classified as any new entity. All three PA cases with BRAF fusion occurred in cerebellum and all four H3K27M altered cases occurred in midline location such as thalamus, brainstem and cervical spinal cord. Six cases which were classified as pediatric-type diffuse high grade gliomas had poor prognosis. Conclusion:Genetic status is associated to tumor location and patients prognosis. Integrated diagnoses are important in pediatric glioma patients.
STMO-3 Mid- to long-term outcome of supratotal resection of IDH1 wild-type glioblastoma based on 11C-methionine PET: a retrospective, single-center study
Authors: Hirono Seiichiro , Ozaki Ko , Kobayashi Masayoshi , Hara Ayaka , Yamaki Tomohiro , Matsutani Tomoo , Iwadate Yasuo
Published: December 2021

Purpose

Mid- to long-term outcome in glioblastoma (GBM) patients following supratotal resection (SupTR), involving complete resection both of contrast-enhancing enhanced (CE) tumors and areas of methionine (Met) uptake on 11C-Met positron emission tomography (Met-PET), are not clarified.

Methods

A retrospective, single-center review was performed in newly diagnosed, IDH1 wild-type GBM patients, comparing SupTR with gross total resection (GTR), in which only CE tumor tissue was completely resected. Only patients who were operated on until November 2019 were included for evaluation of mid- to long-term outcome. Following resection, all patients underwent standard radiotherapy and temozolomide treatment, and were followed for progression-free survival (PFS) and overall survival (OS).

Results

Among the 30 patients included in this study, 7 underwent SupTR and 23 underwent GTR. Awake craniotomy with cortical and subcortical mapping was more frequently performed in the SupTR group than in the GTR group. During the follow-up period, significantly different patterns of disease progression were observed between groups. Although more than 80% of recurrences were local in the GTR group, all recurrences in the SupTR group were distant. Median PFS in the GTR and SupTR groups was 8.8 months (95% confidence interval [CI], 5.2–14.9) and 27.8 months (95% CI, 6.0-not estimable) respectively (p=0.08 by log-rank test). Median OS was 17.7 months (95% CI, 14.2–35.1) in GTR and not reached (95% CI, 30.5-not estimable) in SupTR, respectively; this difference was statistically significant (p=0.03 by log-rank test). No postoperative neurocognitive impairment was observed in SupTR patients.

Conclusion

Compared to GTR alone, SupTR strategy with aggressive resection of both CE tumors and Met uptake area in GBM patients under awake craniotomy with functional preservation results in a survival benefit associated with better local control.