bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the Antibacterial Activity of Crude Extracts Obtained From Cultivation of Native Endophytic Fungi Belonging to a Tropical Montane Rainforest in Colombia
Authors: Charria-Girón Esteban , Espinosa María C. , Zapata-Montoya Andrea , Méndez María J. , Caicedo Juan P. , Dávalos Andrés F. , Ferro Beatriz E. , Vasco-Palacios Aida M. , Caicedo Nelson H.
Published: September 2021

Bioactive secondary metabolite production from endophytic fungi has gained a recurring research focus in recent decades as these microorganisms represent an unexplored biological niche for their diverse biotechnological potential. Despite this focus, studies involving tropical endophytes remain scarce, particularly those isolated from medicinal plants of these ecosystems. In addition, the state of the art of the pharmaceutical industry has experienced stagnation in the past 30years, which has pushed pathogenic infections to get one step ahead, resulting in the development of resistance to existing treatments. Here, five fungal endophytes were isolated from the medicinal plant Otoba gracilipes (Myristicaceae), which corresponded to the genera Xylaria and Diaporthe, and screened to demonstrate the promissory potential of these microorganisms for producing bioactive secondary metabolites with broad-spectrum antibacterial activities. Thus, the evaluation of crude organic extracts obtained from the mycelia and exhaust medium allowed the elucidation of Xylaria sp. and Diaporthe endophytica potential toward providing crude extracellular extracts with promising bioactivities against reference strains of Escherichia coli (ATCC 25922) and Staphylococcus aureus (ATCC 25923), according to the determined half-maximum inhibitory concentration (IC50) with values down to 3.91 and 10.50mg/ml against each pathogen, respectively. Follow-up studies provided insights into the polarity nature of bioactive compounds in the crude extracts through bioactivity guided fractionation using a polymeric resin absorbent alternative extraction procedure. In addition, evaluation of the co-culturing methods demonstrated how this strategy can enhance endophytes biosynthetic capacity and improve their antibacterial potential with a 10-fold decrease in the IC50 values against both pathogens compared to the obtained values in the preliminary evaluations of Xylaria sp. and D. endophytica crude extracts. These results support the potential of Colombian native biodiversity to provide new approaches concerning the global emergence of antibiotics resistance and future production of undiscovered compounds different from the currently used antibiotics classes and simultaneously call for the value of preserving native habitats due to their promising ecosystemic applications in the biotechnological and pharmaceutical industries.
Insight Into Whole Genome of Aeromonas veronii Isolated From Freshwater Fish by Resistome Analysis Reveal Extensively Antibiotic Resistant Traits
Authors: Sakulworakan Rungnapa , Chokmangmeepisarn Putita , Dinh-Hung Nguyen , Sivaramasamy Elayaraja , Hirono Ikuo , Chuanchuen Rungthip , Kayansamruaj Pattanapon , Rodkhum Channarong
Published: September 2021

Aeromonas veronii outbreaks in tilapia farming caused relatively high mortalities, and the bacteria was resistant to many kinds of antimicrobials used in Thailand aquaculture. According to the CLSI standard, the determination of antimicrobials efficacy has been limited to phenotypic analyses, and a genomics study is required. This research aimed to analyze the resistome of A. veronii isolated from diseased tilapia in Chainat, Nong Khai, and Uttaradit provinces in Thailand. A total of 12 isolates of A. veronii were identified based on the gyrB sequencing and then, the MIC values to eight antimicrobials (AMP, AML, GEN, ENR, OXO, OTC, SXT, and FFC) were determined. According to the MIC patterns, whole genome sequencing (WGS) of five representatives and resistome analysis were performed, including 15 genomes of A. veronii isolated from freshwater fish available in the NCBI. All tilapia isolates were susceptible to FFC but resistant to AML and AMP while OTC resistance was the most dominant. In addition to the WGS analysis, 4.5 Mbp of A. veronii was characterized. A total of 20 ARGs were detected by resistome analysis and 16 genes were shared among the A. veronii population. In conclusion, A. veronii strains isolated from tilapia exhibited a resistance to several antimicrobials and multidrug resistance (MDR) which was related to the presence of multiple ARGs. Aeromonas veronii shared the ARGs in their population worldwide with a possibility of a plasmid-mediated acquisition due to the presence of resistance islands.
SNX20AR/MiRNA-301a-3p/SNX20 Axis Associated With Cell Proliferation and Immune Infiltration in Lung Adenocarcinoma
Authors: Yuan Yixiao , Jiang Xiulin , Tang Lin , Wang Juan , Liu Qianqian , Zou Xiaolan , Duan Lincan
Published: September 2021

Lung cancer is the most common tumor with severe morbidity and high mortality. Increasing evidence has demonstrated that SNX20 plays crucial roles in the progression of human cancer. However, the functions and mechanism of SNX20 in LUAD are still barely known. Here, we employ the TCGA, GEO and CCLE databases to examine the expression of SNX20 in human varies cancer, the results shown that SNX20 is down-regulated in lung Adenocarcinoma, SNX20 level was significantly positive correlated with poor prognosis and lung cancer immune cell infiltration. We found that over-expression of SNX20 significantly restrain NSCLC cell proliferation and migration. Subsequently, we discover a network regulating SNX20 in LUAD, further study found that the decreased of the SNX20 likely caused by DNA hypermethylation. Furthermore, we identified that SNX20AR/miRNA-301a-3p mediated decreased of SNX20 correlated with lung cancer progression and cancer immune infiltration in LUAD. Our findings suggested that ncRNAs play a crucial role in the regulatory network of SNX20. Collectively, our findings demonstrate the suppressor roles of the SNX20AR/miRNA-301a-3p/SNX20 axis in Lung Adenocarcinoma, represent that SNX20 have the potential of as an effective therapeutic target in future.
Taking Cellular Heterogeneity Into Consideration When Modeling Astrocyte Involvement in Amyotrophic Lateral Sclerosis Using Human Induced Pluripotent Stem Cells
Authors: Stifani Stefano
Published: September 2021

Astrocytes are a large group of glial cells that perform a variety of physiological functions in the nervous system. They provide trophic, as well as structural, support to neuronal cells. Astrocytes are also involved in neuroinflammatory processes contributing to neuronal dysfunction and death. Growing evidence suggests important roles for astrocytes in non-cell autonomous mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Understanding these mechanisms necessitates the combined use of animal and human cell-based experimental model systems, at least in part because human astrocytes display a number of unique features that cannot be recapitulated in animal models. Human induced pluripotent stem cell (hiPSC)-based approaches provide the opportunity to generate disease-relevant human astrocytes to investigate the roles of these cells in ALS. These approaches are facing the growing recognition that there are heterogenous populations of astrocytes in the nervous system which are not functionally equivalent. This review will discuss the importance of taking astrocyte heterogeneity into consideration when designing hiPSC-based strategies aimed at generating the most informative preparations to study the contribution of astrocytes to ALS pathophysiology.
Brain and Muscle Metabolic Changes by FDG-PET in Stiff Person Syndrome Spectrum Disorders
Authors: Wang Yujie , Sadaghiani Mohammad S. , Tian Fan , Fitzgerald Kathryn C. , Solnes Lilja , Newsome Scott D.
Published: September 2021

Objective: To report clinical characteristics and fluorodeoxyglucose positron emission tomography (FDG-PET) findings in the brain and muscles of individuals with stiff person syndrome (SPS) spectrum disorders (SPSSDs).

Methods: Retrospective cohort study from 1997 to 2018 at Johns Hopkins Hospital identified 170 individuals with SPS or cerebellar ataxia (CA) associated with anti-glutamic acid decarboxylase (anti-GAD)-65 antibodies. Fifty-one underwent FDG-PET, with 50 involving the body and 30 with dedicated brain acquisition. The clinical and immunological profiles were extracted via medical record review. The brain scans were analyzed quantitatively using the NeuroQ software, with comparison with an averaged normal database. The body scans were reviewed qualitatively by a blinded nuclear medicine radiologist.

Results: Mean age of symptom onset was 41.5 years (range 12–75 years). Majority were female (68%) and White (64%). Of the patients, 82% had SPS (majority being classic phenotype), and 18% had CA. Three had a paraneoplastic process. Forty-seven had serum anti-GAD, two with anti-amphiphysin, and one with anti-glycine receptor antibodies. Brain metabolic abnormalities were seen in both SPS and CA, with significant differences between the groups noted in the right superior frontal cortex, right sensorimotor cortex, left inferior parietal cortex, bilateral thalami, vermis, and left cerebellum. Of the patients, 62% demonstrated muscle hypermetabolism, most commonly bilateral, involving the upper extremities or axial muscles. Neither brain nor muscle metabolism was correlated with functional outcomes nor treatments.

Conclusions: Metabolic changes as seen by FDG-PET are present in the brain and muscle in many individuals with SPSSD. Future studies are needed to assess whether FDG-PET can help aid in the diagnosis and/or monitoring of individuals with SPSSD.
Goal-Concordant Care After Severe Acute Brain Injury
Authors: Rutz Voumard Rachel , Dugger Kaley M. , Kiker Whitney A. , Barber Jason , Borasio Gian Domenico , Curtis J. Randall , Jox Ralf J. , Creutzfeldt Claire J.
Published: September 2021

Background: Patients with severe acute brain injury (SABI) lack decision-making capacity, calling on families and clinicians to make goal-concordant decisions, aligning treatment with patient's presumed goals-of-care. Using the family perspective, this study aimed to (1) compare patient's goals-of-care with the care they were receiving in the acute setting, (2) identify patient and family characteristics associated with goal-concordant care, and (3) assess goals-of-care 6 months after SABI.

Methods: Our cohort included patients with SABI in our Neuro-ICU and a Glasgow Coma Scale Score <12 after day 2. Socio-demographic and clinical characteristics were collected through surveys and chart review. At enrollment and again at 6 months, each family was asked if the patient would prefer medical care focused on extending life vs. care focused on comfort and quality of life, and what care the patient is currently receiving. We used multivariate regression to examine the characteristics associated with (a) prioritized goals (comfort/extending life/unsure) and (b) goal concordance.

Results: Among 214 patients, families reported patients' goals-of-care to be extending life in 118 cases (55%), comfort in 71 (33%), and unsure for 25 (12%), while care received focused on extending life in 165 cases (77%), on comfort in 23 (11%) and families were unsure in 16 (7%). In a nominal regression model, prioritizing comfort over extending life was significantly associated with being non-Hispanic White and having worse clinical severity. Most patients who prioritized extending life were receiving family-reported goal-concordant care (88%, 104/118), while most of those who prioritized comfort were receiving goal-discordant care (73%, 52/71). The only independent association for goal concordance was having a presumed goal of extending life at enrollment (OR 23.62, 95% CI 10.19–54.77). Among survivors at 6 months, 1 in 4 family members were unsure about the patient's goals-of-care.

Conclusion: A substantial proportion of patients are receiving unwanted aggressive care in the acute setting after SABI. In the first days, such aggressive care might be justified by prognostic uncertainty. The high rate of families unsure of patient's goals-of-care at 6 months suggests an important need for periodic re-evaluation of prognosis and goals-of-care in the post-acute setting.
Truncal Instability and Titubation in Patients With Acute Encephalopathy With Reduced Subcortical Diffusion
Authors: Kawano Go , Yae Yukako , Sakata Kensuke , Yokochi Takaoki , Imagi Toru , Ohbu Keizo , Matsuishi Toyojiro
Published: September 2021

The present retrospective study aimed to investigate the presence of truncal instability or titubation after the first seizure and second phase in patients with acute encephalopathy with reduced subcortical diffusion (AED). Of the 15 patients with AED who were admitted to our hospital for 3 years and 2 months and had reached developmental milestones for sitting before disease onset, six experienced moderate-to-severe truncal instability while sitting after the first seizure. These patients had a significantly longer first seizure duration and significantly lower GCS scores 12–24 h after the first seizure, as well as significantly higher Tada score and Creatinine and blood glucose levels than those with mild or no truncal instability while in a seated position after the first seizure. Three 1-year-old children with bilateral frontal lobe lesions, particularly in the bilateral prefrontal lobe regions, demonstrated truncal titubation, which has not previously been reported as a clinical feature of AED. Tada score reported to be a predictor of AED prognosis and truncal instability in the sitting position after the first seizure may represent disease severity, but not the specific lesions. Conversely, truncal titubation might be suggestive of bilateral frontal lobe lesions, particularly in patients without severe instability. Further studies on the role of bilateral prefrontal lobe lesions to truncal titubation in patients with AED using more objective evaluation methods, such as stabilometry, are necessary.
Suspected Central Nervous System Infections in HIV-Infected Adults
Authors: Sheybani Fereshte , van de Beek Diederik , Brouwer Matthijs C.
Published: September 2021

Objectives: To study the differential diagnosis of HIV-infected patients with suspected central nervous system (CNS) infections and the association of CD4 counts with the final diagnosis.

Methods: We analyzed HIV-infected patients from a prospective cohort study on the diagnostic accuracy of clinical and laboratory characteristics in adults with suspected CNS infections in an academic hospital in Amsterdam, the Netherlands, who underwent cerebrospinal fluid (CSF) examination.

Results: Thirty-four (9.4%) out of 363 patients with suspected CNS infections were HIV-positive of whom 18 (53%) were diagnosed to have CNS infection, with median CD4 counts of 255 cells/μl. The spectrum of CNS infections consisted of progressive multifocal leukoencephalopathy in three patients (17%); cryptococcal meningoencephalitis, toxoplasma encephalitis, angiostrongylus eosinophilic meningitis, and HIV encephalitis each in two (11%); and cytomegalovirus encephalitis, neurosyphilis, tuberculous meningoencephalitis, histoplasma encephalitis, and varicella-zoster virus meningitis each in one (6%). Clinical characteristics and blood parameters did not differ between HIV-infected patients with CNS infections and other diagnoses. The best predictor for CNS infections was the CSF leukocyte count (AUC = 0.77, 95 CI% 0.61–0.94). The diagnosis of CNS infection was not associated with the CD4 count (median 205 vs. 370, p = 0.21). Two patients (11%) with CNS infections died and two (11%) had neurological sequelae.

Conclusions: Half of the patients with suspected CNS infections are diagnosed with a CNS infection, and this was not related to CD4 counts. The best predictor for CNS infections was the CSF leukocyte count.
What to Believe? Impact of Knowledge and Message Length on Neural Activity in Message Credibility Evaluation
Authors: Kwasniewicz Lukasz , Wojcik Grzegorz M. , Schneider Piotr , Kawiak Andrzej , Wierzbicki Adam
Published: September 2021

Understanding how humans evaluate credibility is an important scientific question in the era of fake news. Message credibility is among crucial aspects of credibility evaluations. One of the most direct ways to understand message credibility is to use measurements of brain activity of humans performing credibility evaluations. Nevertheless, message credibility has never been investigated using such a method before. This article reports the results of an experiment during which we have measured brain activity during message credibility evaluation, using EEG. The experiment allowed for identification of brain areas that were active when participant made positive or negative message credibility evaluations. Based on experimental data, we modeled and predicted human message credibility evaluations using EEG brain activity measurements with F1 score exceeding 0.7.
Auditory, Visual, and Cross-Modal Mismatch Negativities in the Rat Auditory and Visual Cortices
Authors: Shiramatsu Tomoyo Isoguchi , Mori Kanato , Ishizu Kotaro , Takahashi Hirokazu
Published: September 2021

When the brain tries to acquire an elaborate model of the world, multisensory integration should contribute to building predictions based on the various pieces of information, and deviance detection should repeatedly update these predictions by detecting “errors” from the actual sensory inputs. Accumulating evidence such as a hierarchical organization of the deviance-detection system indicates that the deviance-detection system can be interpreted in the predictive coding framework. Herein, we targeted mismatch negativity (MMN) as a type of prediction-error signal and investigated the relationship between multisensory integration and MMN. In particular, we studied whether and how cross-modal information processing affected MMN in rodents. We designed a new surface microelectrode array and simultaneously recorded visual and auditory evoked potentials from the visual and auditory cortices of rats under anesthesia. Then, we mapped MMNs for five types of deviant stimuli: single-modal deviants in (i) the visual oddball and (ii) auditory oddball paradigms, eliciting single-modal MMN; (iii) congruent audio-visual deviants, (iv) incongruent visual deviants, and (v) incongruent auditory deviants in the audio-visual oddball paradigm, eliciting cross-modal MMN. First, we demonstrated that visual MMN exhibited deviance detection properties and that the first-generation focus of visual MMN was localized in the visual cortex, as previously reported in human studies. Second, a comparison of MMN amplitudes revealed a non-linear relationship between single-modal and cross-modal MMNs. Moreover, congruent audio-visual MMN exhibited characteristics of both visual and auditory MMNs—its latency was similar to that of auditory MMN, whereas local blockage of N-methyl-D-aspartic acid receptors in the visual cortex diminished it as well as visual MMN. These results indicate that cross-modal information processing affects MMN without involving strong top-down effects, such as those of prior knowledge and attention. The present study is the first electrophysiological evidence of cross-modal MMN in animal models, and future studies on the neural mechanisms combining multisensory integration and deviance detection are expected to provide electrophysiological evidence to confirm the links between MMN and predictive coding theory.
Left Hemisphere Dominance for Negative Facial Expressions: The Influence of Task
Authors: Burgund E. Darcy
Published: September 2021

Major theories of hemisphere asymmetries in facial expression processing predict right hemisphere dominance for negative facial expressions of disgust, fear, and sadness, however, some studies observe left hemisphere dominance for one or more of these expressions. Research suggests that tasks requiring the identification of six basic emotional facial expressions (angry, disgusted, fearful, happy, sad, and surprised) are more likely to produce left hemisphere involvement than tasks that do not require expression identification. The present research investigated this possibility in two experiments that presented six basic emotional facial expressions to the right or left hemisphere using a divided-visual field paradigm. In Experiment 1, participants identified emotional expressions by pushing a key corresponding to one of six labels. In Experiment 2, participants detected emotional expressions by pushing a key corresponding to whether an expression was emotional or not. In line with predictions, fearful facial expressions exhibited a left hemisphere advantage during the identification task but not during the detection task. In contrast to predictions, sad expressions exhibited a left hemisphere advantage during both identification and detection tasks. In addition, happy facial expressions exhibited a left hemisphere advantage during the detection task but not during the identification task. Only angry facial expressions exhibited a right hemisphere advantage, and this was only observed when data from both experiments were combined. Together, results highlight the influence of task demands on hemisphere asymmetries in facial expression processing and suggest a greater role for the left hemisphere in negative expressions than predicted by previous theories.
Effect of Heat Treatment on the Property, Structure, and Aggregation of Skim Milk Proteins
Authors: Li Hongbo , Zhao Tingting , Li Hongjuan , Yu Jinghua
Published: September 2021

To study the mechanism of heat-induced protein aggregates, skim milk was heated at 55, 65, 75, 85, and 95°C for 30 s. Then, the sulfhydryl content, surface hydrophobicity, and secondary structure of heat-treated skim milk were studied. Treating skim milk at different temperatures induced a decrease in sulfhydryl content (75.9% at 95°C) and an increase in surface hydrophobicity (44% at 95°C) with a disrupted secondary structure containing random coil, β-sheet, and β-turn of skim milk proteins. The change in these properties facilitated aggregate formation through disulfide bonds and hydrophobicity interaction. Microstructural observation also showed a higher degree of aggregation when skim milk was heated at 85 and 95°C. The result of two-dimensional polyacrylamide gel electrophoresis demonstrated that the aggregates consisted of a high proportion of κ-casein, β-lactoglobulin, and other whey proteins.
The Impact of Citrus-Tea Cofermentation Process on Chemical Composition and Contents of Pu-Erh Tea: An Integrated Metabolomics Study
Authors: Xu Ya , Liang Pu-Lin , Chen Xue-Lian , Gong Ming-Jiong , Zhang Liang , Qiu Xiao-Hui , Zhang Jing , Huang Zhi-Hai , Xu Wen
Published: September 2021

Ganpu tea, an emerging pu-erh compound tea, which is cofermented with the peel of Citrus reticulata “Chachi,” has been widely favored by Chinese consumers due to its potential health effects and distinct flavor and taste. So far, the influence of this cofermentation procedure on the chemical profile of pu-erh tea has barely been addressed yet. In this work, an ultra-high-performance liquid chromatography-Q Exactive Orbitrap mass spectrometry (UHPLC-QE Orbitrap MS)-based qualitative and quantitative method combined with multivariate analysis was conducted to comprehensively investigate the chemical changes in pu-erh tea after cofermented with Citrus peel. A total of 171 compounds were identified based on a three-level strategy, among which seven phenolic acids, 11 flavan-3-ols, and 27 flavonoids and flavonoid glycosides were identified from pu-erh tea for the first time. Eighty-nine main constituents were selected for further quantitative analysis using a validated method. Both the principal component analysis (PCA) of untargeted metabolomics and orthogonal partial least squares discriminant analysis (OPLS-DA) models of targeted components revealed the significant chemical profile disparity between the raw pu-erh tea and Ganpu tea. It showed that Citrus tea cofermentation process significantly decreased the total contents of phenolic acids, flavan-3-ols, and flavonoid aglycones, while most of the quercetin glycosides and myricetin glycosides as well as the vitexin were significantly increased. In addition, hesperidin, a flavonoid glycoside only existed in Citrus, was first found in pu-erh tea after cofermented with Citrus. This study clearly profiled the chemical composition and content changes of pu-erh tea after cofermented with Citrus peel, which revealed that Citrus tea cofermentation process further accelerated the fermentation of pu-erh tea and improved the unique flavor of tea.
Prognostic Value of Preoperative NLR and Vascular Reconstructive Technology in Patients With Pancreatic Cancer of Portal System Invasion: A Real World Study
Authors: Zhou Lin , Wang Jing , Zhang Xin-xue , Lyu Shao-cheng , Pan Li-chao , Du Guo-sheng , Lang Ren , He Qiang
Published: September 2021

The purpose was aimed to establish a simple computational model to predict tumor prognosis by combining neutrophil to lymphocyte Ratio (NLR) and biomarkers of oncological characteristics in patients undergoing vascular reconstructive radical resection of PDAC. The enrolled patients was divided into high or low NLR group with the cutoff value determined by the receiver operator characteristic (ROC) curve. Different vascular anastomoses were selected according to the Chaoyang classification of PDAC. Survival rates were calculated using the Kaplan-Meier and evaluated with the log-rank test. Cox risk regression model was used to analyze the independent risk factors for prognostic survival. The optimal cut-off value of NRL was correlated with the differentiation, tumor size, TNM stage and distant metastasis of advanced PDAC. A curative resection with vascular reconstructive of advanced PDAC according to Chaoyang classification can obviously improve the survival benefits. Cox proportional hazards demonstrated higher evaluated NLR, incisal margin R1 and lymphatic metastasis were the independent risk predictor for prognosis with the HR > 2, meanwhile, age beyond 55, TNM stage of III-IV or Tumor size > 4cm were also the obvious independent risk predictor for prognosis with the HR ≤ 2. The advanced PADC patients marked of RS group (3 < RS ≤ 6) showed no more than 24 months of survival time according to RS model based on the six independent risk predictors. Vascular reconstruction in radical resection of advanced PDAC improved survival, higher elevated NLR (>2.90) was a negative predictor of DFS and OS in those patients accompanying portal system invasion.
Radiomics Analysis of Fat-Saturated T2-Weighted MRI Sequences for the Prediction of Prognosis in Soft Tissue Sarcoma of the Extremities and Trunk Treated With Neoadjuvant Radiotherapy
Authors: Chen Silin , Li Ning , Tang Yuan , Chen Bo , Fang Hui , Qi Shunan , Lu Ninging , Yang Yong , Song Yongwen , Liu Yueping , Wang Shulian , Li Ye-xiong , Jin Jing
Published: September 2021

Purpose

To create a prognostic prediction radiomics model for soft tissue sarcoma (STS) of the extremities and trunk treated with neoadjuvant radiotherapy.

Methods

This study included 62 patients with STS of the extremities and trunk who underwent magnetic resonance imaging (MRI) before neoadjuvant radiotherapy. After tumour segmentation and preprocessing, 851 radiomics features were extracted. The radiomics score was constructed according to the least absolute shrinkage and selection operator (LASSO) method. Survival analysis (disease-free survival; DFS) was performed using the log-rank test and Cox’s proportional hazards regression model. The nomogram model was established based on the log-rank test and Cox regression model. Harrell’s concordance index (C-index), calibration curve and receiver operating characteristic (ROC) curve analysis were used to evaluate the prognostic factors. The clinical utility of the model was assessed by decision curve analysis (DCA).

Results

The univariate survival analysis showed that tumour location (p = 0.032), clinical stage (p = 0.022), tumour size (p = 0.005) and the radiomics score were correlated with DFS (p < 0.05). The multivariate analysis showed that tumour location, tumour size, and the radiomics score were independent prognostic factors for DFS (p < 0.05). The combined clinical-radiomics model based on the multivariate analysis showed the best predictive ability for DFS (C-index: 0.781; Area Under Curve: 0.791). DCA revealed that the use of the radiomics score-based nomogram was associated with better benefit gains relative to the prediction of 2-year DFS events than other models in the threshold probability range between 0.12 and 0.38.

Conclusion

The radiomics score from pretreatment MRI is an independent prognostic factor for DFS in patients with STS of the extremities and trunk. The radiomics score-based nomogram could improve prognostic stratification ability and thus contribute to individualized therapy for STS patients.
An Investigation of Non-Coplanar Volumetric Modulated Radiation Therapy for Locally Advanced Unresectable Pancreatic Cancer Using a Trajectory Optimization Method
Authors: Wang Gong , Wang Hao , Zhuang Hongqing , Yang Ruijie
Published: September 2021

Purpose

This study was conducted in order to develop a trajectory optimization algorithm for non-coplanar volumetric modulated arc therapy (VMAT) and investigate the potential of organs at risk (OARs) sparing in locally advanced pancreatic cancer patients using non-coplanar VMAT.

Methods and Materials

Firstly, a cost map that represents the ray–OAR voxel intersections at each source position was generated using a ray-tracing algorithm. A graph search algorithm was then used to determine the least-cost path from the cost map. Lastly, full arcs or partial arcs were selected based on the least-cost path to generate the non-coplanar VMAT (ncVMAT) trajectories. Clinical coplanar VMAT (coVMAT) plans for 11 patients diagnosed with locally advanced unresectable pancreatic cancer (LAPC) receiving 45 to 70 Gy in 25 fractions were replanned using non-coplanar VMAT trajectories. Both coplanar and non-coplanar plans were normalized to cover 95% of the PTV45 Gy volume with a prescription dose of 45 Gy. The conformity index (CI), homogeneity index (HI), PTV coverage, and dose to the OARs were compared between coVMAT and ncVMAT plans.

Results

With ncVMAT, the mean coverage of PTV50 Gy, PTV54 Gy, PTV60 Gy, and PTV70 Gy increased significantly. The mean conformity index of PTV45 Gy, PTV54 Gy, and PTV70 Gy was also improved in the ncVMAT plans. Compared with coVMAT plans, the ncVMAT plans resulted in significantly lower doses to the spinal cord, bilateral kidneys, stomach, and duodenum. The maximum dose to the spinal cord decreased by 6.11%. The mean dose to the left and right kidneys decreased by an average of 5.52% and 11.71%, respectively. The Dmax, Dmean, and D15% of the stomach were reduced by an average of 7.45%, 15.82%, and 16.79%, separately. The D15% and Dmean of the duodenum decreased 6.38% and 5.64%, respectively.

Conclusion

A trajectory optimization algorithm was developed for non-coplanar VMAT. Compared with conventional coplanar VMAT, non-coplanar VMAT resulted in improved coverage and conformity to the targets. The sparing of OARs was significantly improved in non-coplanar VMAT compared with coVMAT plans for locally advanced pancreatic cancer.
Muscle Loss During Androgen Deprivation Therapy Is Associated With Higher Risk of Non-Cancer Mortality in High-Risk Prostate Cancer
Authors: Chiang Pai-Kai , Tsai Wei-Kung , Chiu Allen Wen-Hsiang , Lin Jhen-Bin , Yang Feng-Yi , Lee Jie
Published: September 2021

The changes in body composition are early adverse effects of androgen deprivation therapy (ADT); however, their prognostic impact remains unclear in prostate cancer. This study aimed to evaluate the association between body composition changes and survival in patients with high-risk prostate cancer. We measured the skeletal muscle index (SMI) and total adipose tissue index (TATI) at the L3 vertebral level using computed tomography at baseline and within one year after initiating ADT in 125 patients with high-risk prostate cancer treated with radiotherapy and ADT between 2008 and 2018. Non-cancer mortality predictors were identified using Cox regression models. The median follow-up was 49 months. Patients experienced an average SMI loss of 5.5% over 180 days (95% confidence interval: -7.0 to -4.0; p<0.001) and TATI gain of 12.6% over 180 days (95% confidence interval: 9.0 to 16.2; p<0.001). Body mass index changes were highly and weakly correlated with changes in TATI and SMI, respectively (Spearman ρ for TATI, 0.78, p<0.001; ρ for SMI, 0.27, p=0.003). As a continuous variable, each 1% decrease in SMI was independently associated with a 9% increase in the risk of non-cancer mortality (hazard ratio: 1.09; p=0.007). Moreover, the risk of non-cancer mortality increased 5.6-fold in patients with SMI loss ≥5% compared to those with unchanged SMI (hazard ratio: 5.60; p=0.03). Body mass index and TATI were not associated with non-cancer mortality. Muscle loss during ADT is occult, independent of weight change, and independently associated with increased non-cancer mortality in patients with high-risk prostate cancer.
Identification of Potential Biomarkers for Liver Cancer Through Gene Mutation and Clinical Characteristics
Authors: Cui Yunlong , Li Hua , Zhan Hongjie , Han Tao , Dong Yixuan , Tian Caijuan , Guo Yixian , Yan Fang , Dai Dong , Liu Pengfei
Published: September 2021

Liver cancer is a common malignant tumor worldwide, which is a serious threat to the health of people. We try to investigate some mutations and clinical indicators as candidate markers for the development of liver cancer through targeted region capture technology combined with next-generation sequencing. We collected peripheral blood and liver cancer tissue samples from 32 liver patients concurrently. The SeqCap EZ Prime Choice Probe was used to perform the targeted enrichment; this probe captures 1,000 known cancer-associated genes. We calculated the tumor mutation burden (TMB) for each patient. The high-frequency mutations and these relative genes were identified. Eventually, survival analysis was performed based on the mutations and clinical indicators. In 32 liver patients, a total of 29 high-frequency mutations were investigated. They were located in 25 genes, which were enriched in 9 cellular components (CCs), 6 molecular functions (MFs), and 21 biological processes (BPs). Among them, EZH2 c.1544A>G and CCND1 c.839A>T had the highest mutation frequency (5/32). In the protein–protein interaction (PPI) network, EZH2-DNMT3A, NOTCH1-CCND1, and ABL1-CCND1 were the top three pairs. The survival analysis showed that there were significant differences in progression-free survival (PFS) and overall survival (OS) between the Karnofsky performance score (KPS) groups. The PFS and OS in the TMB high group were higher than those in the TMB low group. OS and tumor stage had a remarkable relationship. In conclusion, EZH2 c.1544A>G and CCND1 c.839A>T might be potential biomarkers of liver cancer. TMB might be used as a prognosis and survival indicator of liver cancer.
A Phase II Trial of Adjuvant Durvalumab Following Trimodality Therapy for Locally Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma: A Big Ten Cancer Research Consortium Study
Authors: Mamdani Hirva , Schneider Bryan , Perkins Susan M. , Burney Heather N. , Kasi Pashtoon Murtaza , Abushahin Laith I. , Birdas Thomas , Kesler Kenneth , Watkins Tracy M. , Badve Sunil S. , Radovich Milan , Jalal Shadia I.
Published: September 2021

Background

Most patients with resectable locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma (AC) receive concurrent chemoradiation (CRT) followed by esophagectomy. The majority of patients do not achieve pathologic complete response (pCR) with neoadjuvant CRT, and the relapse rate is high among these patients.

Methods

We conducted a phase II study (ClinicalTrials.gov Identifier: NCT02639065) evaluating the efficacy and safety of PD-L1 inhibitor durvalumab in patients with locally advanced esophageal and GEJ AC who have undergone neoadjuvant CRT followed by R0 resection with evidence of persistent residual disease in the surgical specimen. Patients received durvalumab 1500 mg IV every 4 weeks for up to 1 year. The primary endpoint was 1-year relapse free survival (RFS). Secondary endpoint was safety and tolerability of durvalumab following trimodality therapy. Exploratory endpoints included correlation of RFS with PD-L1 expression, HER-2 expression, and tumor immune cell population.

Results

Thirty-seven patients were enrolled. The majority (64.9%) had pathologically positive lymph nodes. The most common treatment related adverse events were fatigue (27%), diarrhea (18.9%), arthralgia (16.2%), nausea (16.2%), pruritus (16.2%), cough (10.8%), and increase in AST/ALT/bilirubin (10.8%). Three (8.1%) patients developed grade 3 immune mediated adverse events. One-year RFS was 73% (95% CI, 56–84%) with median RFS of 21 months (95% CI, 14–40.4 months). Patients with GEJ AC had a trend toward superior 1-year RFS compared to those with esophageal AC (83% vs. 63%, p = 0.1534). There was a numerical trend toward superior 1-year RFS among patients with PD-L1 positive disease compared to those with PD-L1 negative disease, using CPS of ≥10 (100% vs. 66.7%, p = 0.1551) and ≥1 (84.2% vs. 61.1%, p = 0.1510) cutoffs. A higher relative proportion of M2 macrophages and CD4 memory activated T cells was associated with improved RFS (HR = 0.16; 95% CI, 0.05–0.59; p = 0.0053; and HR = 0.37; 95% CI, 0.15–0.93, p = 0.0351, respectively).

Conclusions

Adjuvant durvalumab in patients with residual disease in the surgical specimen following trimodality therapy for locally advanced esophageal and GEJ AC led to clinically meaningful improvement in 1-year RFS compared to historical control rate. Higher PD-L1 expression may have a correlation with the efficacy of durvalumab in this setting. Higher proportion of M2 macrophages and CD4 memory activated T cells was associated with superior RFS.
Comparison of the Relative Diagnostic Performance of [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT for the Detection of Bone Metastasis in Patients With Different Cancers
Authors: Wu Junhao , Wang Yingwei , Liao Taiping , Rao Zijuan , Gong Weidong , Ou Lei , Chen Yue , Zhang Chunyin
Published: September 2021

Purpose

The present retrospective analysis sought to compare the relative diagnostic efficacy of [68Ga]Ga-DOTA-FAPI-04 to that of [18F]FDG PET/CT as a means of detecting bone metastases in patients with a range of cancer types.

Materials

In total, 30 patients with bone metastases associated with different underlying malignancies were retrospectively enrolled. All patients had undergone [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT, and the McNemar test was used to compare the relative diagnostic performance of these two imaging modalities. The maximum standard uptake value (SUVmax) was used to quantify radiotracer uptake by metastatic lesions, with the relative uptake associated with these two imaging strategies being compared via the Mann-Whitney U test. The cohort was further respectively divided into two (osteolytic and osteoblastic bone metastases) and three clinical subgroups (lung cancer, thyroid cancer, and liver cancer).

Results

[68Ga]Ga-DOTA-FAPI-04 PET/CT was found to be significantly more sensitive as a means of diagnosing bone metastases relative to [18F]FDG PET/CT ([109/109] 100% vs [89/109] 81.7%; P< 0.01), consistent with the significantly increased uptake of [68Ga]Ga-DOTA-FAPI-04 by these metastatic lesions relative to that of [18F]FDG (n=109, median SUVmax, 9.1 vs. 4.5; P< 0.01). [68Ga]Ga-DOTA-FAPI-04 accumulation was significantly higher than that of [18F]FDG in both osteolytic (n=66, median SUVmax, 10.6 vs 6.1; P < 0.01), and osteoblastic metastases (n=43, median SUVmax, 7.7 vs 3.7; P < 0.01). [68Ga]Ga-DOTA-FAPI-04 uptakes were significantly higher than that of [18F]FDG in bone metastases from lung cancer (n = 62, median SUVmax, 10.7 vs 5.2; P < 0.01), thyroid cancer (n = 18, median SUVmax, 5.65 vs 2.1; P < 0.01) and liver cancer (n = 12, median SUVmax, 5.65 vs 3.05; P < 0.01). However, [68Ga]Ga-DOTA-FAPI-04 detected 10 false-positive lesions, while only 5 false-positive were visualized by [18F]FDG PET/CT.

Conclusion

[68Ga]Ga-DOTA-FAPI-04 PET/CT exhibits excellent diagnostic performance as a means of detecting bone metastases, and is superior to [18F]FDG PET/CT in this diagnostic context. Furthermore, [68Ga]Ga-DOTA-FAPI-04 tracer uptake levels are higher than those of [18F]FDG for most bone metastases. However, owing to the potential for false-positive bone lesions, it is critical that physicians interpret all CT findings with caution to ensure diagnostic accuracy.
Ceramide Regulates Anti-Tumor Mechanisms of Erianin in Androgen-Sensitive and Castration-Resistant Prostate Cancers
Authors: Trapika I Gusti Md Gde Surya C. , Liu Xin Tracy , Chung Long Hoa , Lai Felcia , Xie Chanlu , Zhao Yang , Cui Shaohui , Chen Jinbiao , Tran Collin , Wang Qian , Zhang Shubiao , Don Anthony S. , Li George Qian , Hanrahan Jane R. , Qi Yanfei
Published: September 2021

Prostate cancer is the second most prevalent malignancy worldwide. In the early stages, the development of prostate cancer is dependent on androgens. Over time with androgen deprivation therapy, 20% of prostate cancers progress to a castration-resistant form. Novel treatments for prostate cancers are still urgently needed. Erianin is a plant-derived bibenzyl compound. We report herein that erianin exhibits anti-tumor effects in androgen-sensitive and castration-resistant prostate cancer cells through different mechanisms. Erianin induces endoplasmic reticulum stress-associated apoptosis in androgen-sensitive prostate cancer cells. It also triggers pro-survival autophagic responses, as inhibition of autophagy predisposes to apoptosis. In contrast, erianin fails to induce apoptosis in castration-resistant prostate cancer cells. Instead, it results in cell cycle arrest at the M phase. Mechanistically, C16 ceramide dictates differential responses of androgen-sensitive and castration-resistant prostate cancer cells to erianin. Erianin elevates C16 ceramide level in androgen-sensitive but not castration-resistant prostate cancer cells. Overexpression of ceramide synthase 5 that specifically produces C16 ceramide enables erianin to induce apoptosis in castration-resistant prostate cancer cells. Our study provides both experimental evidence and mechanistic data showing that erianin is a potential treatment option for prostate cancers.
Preoperative CT-Based Deep Learning Model for Predicting Risk Stratification in Patients With Gastrointestinal Stromal Tumors
Authors: Kang Bing , Yuan Xianshun , Wang Hexiang , Qin Songnan , Song Xuelin , Yu Xinxin , Zhang Shuai , Sun Cong , Zhou Qing , Wei Ying , Shi Feng , Yang Shifeng , Wang Ximing
Published: September 2021

Objective

To develop and evaluate a deep learning model (DLM) for predicting the risk stratification of gastrointestinal stromal tumors (GISTs).

Methods

Preoperative contrast-enhanced CT images of 733 patients with GISTs were retrospectively obtained from two centers between January 2011 and June 2020. The datasets were split into training (n = 241), testing (n = 104), and external validation cohorts (n = 388). A DLM for predicting the risk stratification of GISTs was developed using a convolutional neural network and evaluated in the testing and external validation cohorts. The performance of the DLM was compared with that of radiomics model by using the area under the receiver operating characteristic curves (AUROCs) and the Obuchowski index. The attention area of the DLM was visualized as a heatmap by gradient-weighted class activation mapping.

Results

In the testing cohort, the DLM had AUROCs of 0.90 (95% confidence interval [CI]: 0.84, 0.96), 0.80 (95% CI: 0.72, 0.88), and 0.89 (95% CI: 0.83, 0.95) for low-malignant, intermediate-malignant, and high-malignant GISTs, respectively. In the external validation cohort, the AUROCs of the DLM were 0.87 (95% CI: 0.83, 0.91), 0.64 (95% CI: 0.60, 0.68), and 0.85 (95% CI: 0.81, 0.89) for low-malignant, intermediate-malignant, and high-malignant GISTs, respectively. The DLM (Obuchowski index: training, 0.84; external validation, 0.79) outperformed the radiomics model (Obuchowski index: training, 0.77; external validation, 0.77) for predicting risk stratification of GISTs. The relevant subregions were successfully highlighted with attention heatmap on the CT images for further clinical review.

Conclusion

The DLM showed good performance for predicting the risk stratification of GISTs using CT images and achieved better performance than that of radiomics model.
Assessing Anticoagulation in Neonates With Congenital Diaphragmatic Hernia During Extracorporeal Membrane Oxygenation: Does Anti-Factor Xa or Thromboelastometry Provide Additional Benefit?
Authors: Perez Ortiz Alba , Dempfle Carl E. , Jung Toni , Doniga Thalia , Weiß Christel , Hetjens Svetlana , Schaible Thomas , Rafat Neysan
Published: September 2021

Objective:The optimal management of anticoagulation in neonatal/pediatric patients during extracorporeal membrane oxygenation (ECMO) has not been established yet and varies greatly among ECMO centers worldwide. Therefore, we aimed to assess whether the use of anti-factor Xa assay and/or thromboelastometry correlate better than activated clotting time with heparin dose in newborns with congenital diaphragmatic hernia during ECMO. We also examined whether these coagulation assays correlate with thrombotic and/or hemorrhagic complications, when the management of anticoagulation is based only on activated clotting time values.

Methods:A prospective observational study in a neonatal ECMO center was conducted. We included all neonates with congenital diaphragmatic hernia born in our institution between March 2018 and January 2019 and requiring support with venoarterial ECMO. A total of 26 ECMO runs were analyzed. During the study, the heparin dose was still adjusted according to activated clotting time values. Measurements of anti-factor Xa assay, activated partial thromboplastin time, and a thromboelastometry from the same blood specimen were performed twice a day.

Results:Anti-factor Xa levels showed a moderate correlation with heparin dose, whereas the other tests showed a weak correlation. Four patients (17.4%) had thrombotic complications, 2 patients (8.7%) experienced life-threatening bleeding, and in 11 patients (47.8%) disseminated intravascular coagulation (DIC) occurred. Anti-factor Xa levels were lower in the group with thrombotic complications (0.23 vs. 0.27 IU/ml;p= 0.002), while activated partial thromboplastin time was higher in the group with hemorrhagic complications (69.4 s vs. 59.8 s;p= 0.01). In patients experiencing DIC, heparin dose and anti-factor Xa levels were lower, while no difference in activated clotting time and clotting time in INTEM and INTEM-HEPTEM were shown.

Conclusions:Anti-factor Xa levels correlate better to heparin dose than activated clotting time. The use of anti-factor Xa assay instead of activated clotting time for dosing of unfractionated heparin could reduce thrombotic complications in neonates with congenital diaphragmatic hernia on ECMO support. The thromboelastometry showed no additional benefit for this purpose.