bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole Genome Sequencing of Extended-Spectrum- and AmpC- β-Lactamase-Positive Enterobacterales Isolated From Spinach Production in Gauteng Province, South Africa
Authors: Richter Loandi , du Plessis Erika M. , Duvenage Stacey , Allam Mushal , Ismail Arshad , Korsten Lise
Published: October 2021

The increasing occurrence of multidrug-resistant (MDR) extended-spectrum β-lactamase- (ESBL) and/or AmpC β-lactamase- (AmpC) producing Enterobacterales in irrigation water and associated irrigated fresh produce represents risks related to the environment, food safety, and public health. In South Africa, information about the presence of ESBL/AmpC-producing Enterobacterales from non-clinical sources is limited, particularly in the water–plant-food interface. This study aimed to characterize 19 selected MDR ESBL/AmpC-producing Escherichia coli (n=3), Klebsiella pneumoniae (n=5), Serratia fonticola (n=10), and Salmonella enterica (n=1) isolates from spinach and associated irrigation water samples from two commercial spinach production systems within South Africa, using whole genome sequencing (WGS). Antibiotic resistance genes potentially encoding resistance to eight different classes were present, with blaCTX-M-15 being the dominant ESBL encoding gene and blaACT-types being the dominant AmpC encoding gene detected. A greater number of resistance genes across more antibiotic classes were seen in all the K. pneumoniae strains, compared to the other genera tested. From one farm, blaCTX-M-15-positive K. pneumoniae strains of the same sequence type 985 (ST 985) were present in spinach at harvest and retail samples after processing, suggesting successful persistence of these MDR strains. In addition, ESBL-producing K. pneumoniae ST15, an emerging high-risk clone causing nosocomical outbreaks worldwide, was isolated from irrigation water. Known resistance plasmid replicon types of Enterobacterales including IncFIB, IncFIA, IncFII, IncB/O, and IncHI1B were observed in all strains following analysis with PlasmidFinder. However, blaCTX-M-15 was the only β-lactamase resistance gene associated with plasmids (IncFII and IncFIB) in K. pneumoniae (n=4) strains. In one E. coli and five K. pneumoniae strains, integron In191 was observed. Relevant similarities to human pathogens were predicted with PathogenFinder for all 19 strains, with a confidence of 0.635–0.721 in S. fonticola, 0.852–0.931 in E. coli, 0.796–0.899 in K. pneumoniae, and 0.939 in the S. enterica strain. The presence of MDR ESBL/AmpC-producing E. coli, K. pneumoniae, S. fonticola, and S. enterica with similarities to human pathogens in the agricultural production systems reflects environmental and food contamination mediated by anthropogenic activities, contributing to the spread of antibiotic resistance genes.
Genome-Based Taxonomic Rearrangement of the Order Geobacterales Including the Description of Geomonas azotofigens sp. nov. and Geomonas diazotrophica sp. nov.
Authors: Xu Zhenxing , Masuda Yoko , Wang Xueding , Ushijima Natsumi , Shiratori Yutaka , Senoo Keishi , Itoh Hideomi
Published: October 2021

Geobacterales is a recently proposed order comprising members who originally belonged to the well-known family Geobacteraceae, which is a key group in terrestrial ecosystems involved in biogeochemical cycles and has been widely investigated in bioelectrochemistry and bioenergy fields. Previous studies have illustrated the taxonomic structure of most members in this group based on genomic phylogeny; however, several members are still in a pendent or chaotic taxonomic status owing to the lack of genome sequences. To address this issue, we performed this taxonomic reassignment using currently available genome sequences, along with the description of two novel paddy soil-isolated strains, designated Red51T and Red69T, which are phylogenetically located within this order. Phylogenomic analysis based on 120 ubiquitous single-copy proteins robustly separated the species Geobacter luticola from other known genera and placed the genus Oryzomonas (fam. Geobacteraceae) into the family ‘Pseudopelobacteraceae’; thus, a novel genus Geomobilimonas is proposed, and the family ‘Pseudopelobacteraceae’ was emended. Moreover, genomic comparisons with similarity indexes, including average amino acid identity (AAI), percentage of conserved protein (POCP), and average nucleotide identity (ANI), showed proper thresholds as genera boundaries in this order with values of 70%, 65%, and 74% for AAI, POCP, and ANI, respectively. Based on this, the three species Geobacter argillaceus, Geobacter pelophilus, and Geobacter chapellei should be three novel genera, for which the names Geomobilibacter, Geoanaerobacter, and Pelotalea are proposed, respectively. In addition, the two novel isolated strains phylogenetically belonged to the genus Geomonas, family Geobacteraceae, and shared genomic similarity values higher than those of genera boundaries, but lower than those of species boundaries with each other and their neighbors. Taken together with phenotypic and chemotaxonomic characteristics similar to other Geomonas species, these two strains, Red51T and Red69T, represent two novel species in the genus Geomonas, for which the names Geomonas azotofigens sp. nov. and Geomonas diazotrophica sp. nov. are proposed, respectively.
Geography-Driven Evolution of Potato Virus A Revealed by Genetic Diversity Analysis of the Complete Genome
Authors: Zhang Wei , Sun Xuhong , Wei Xuyan , Gao Yanling , Song Jiling , Bai Yanju
Published: October 2021

Potato virus A (PVA), a member of the genus Potyvirus, is an important potato pathogen that causes 30%–40% yield reduction to global potato production. Knowledge on the genetic structure and the evolutionary forces shaping the structure of this pathogen is limited but vital in developing effective management strategies. In this study, we investigated the population structure and molecular evolution of PVA by analyzing novel complete genomic sequences from Chinese isolates combined with available sequences from Europe, South America, Oceania, and North America. High nucleotide diversity was discovered among the populations studied. Pairwise FST values between geographical populations of PVA ranged from 0.22 to 0.46, indicating a significant spatial structure for this pathogen. Although purifying selection was detected at the majority of polymorphic sites, significant positive selection was identified in the P1, NIa, and NIb proteins, pointing to adaptive evolution of PVA. Further phylogeny–trait association analysis showed that the clustering of PVA isolates was significantly correlated with geographic regions, suggesting that geography-driven adaptation may be an important determinant of PVA diversification.
First Report of blaIMP–4 and blaSRT–2 Coproducing Serratia marcescens Clinical Isolate in China
Authors: Huang Xiangning , Shen Siquan , Shi Qingyu , Ding Li , Wu Shi , Han Renru , Zhou Xun , Yu Hua , Hu Fupin
Published: October 2021

Carbapenem-resistant Enterobacterales (CRE) has become a major therapeutic concern in clinical settings, and carbapenemase genes have been widely reported in various bacteria. In Serratia marcescens, class A group carbapenemases including SME and KPC were mostly identified. However, there are few reports of metallo-β-lactamase-producing S. marcescens. Here, we isolated a carbapenem-resistant S. marcescens (S378) from a patient with asymptomatic urinary tract infection which was then identified as an IMP-4-producing S. marcescens at a tertiary hospital in Sichuan Province in southwest of China. The species were identified using MALDI-TOF MS, and carbapenemase-encoding genes were detected using PCR and DNA sequencing. The results of antimicrobial susceptibility testing by broth microdilution method indicated that the isolate S. marcescens S378 was resistant to meropenem (MIC = 32 μg/ml) and imipenem (MIC = 64 μg/ml) and intermediate to aztreonam (MIC = 8 μg/ml). The complete genomic sequence of S. marcescens was identified using Illumina (Illumina, San Diego, CA, United States) short-read sequencing (150 bp paired-end reads); five resistance genes had been identified, including blaIMP–4, blaSRT–2, aac(6′)-Ic, qnrS1, and tet(41). Conjugation experiments indicated that the blaIMP–4-carrying plasmid pS378P was conjugative. Complete sequence analysis of the plasmid pS378P bearing blaIMP–4 revealed that it was a 48,780-bp IncN-type plasmid with an average GC content of 50% and was nearly identical to pP378-IMP (99% nucleotide identity and query coverage).
Development and Verification of an Immune-Related Gene Pairs Prognostic Signature in Hepatocellular Carcinoma
Authors: Feng Xiaofei , Mu Shanshan , Ma Yao , Wang Wenji
Published: October 2021

With the increasing prevalence of Hepatocellular carcinoma (HCC) and the poor prognosis of immunotherapy, reliable immune-related gene pairs (IRGPs) prognostic signature is required for personalized management and treatment of patients. Gene expression profiles and clinical information of HCC patients were obtained from the TCGA and ICGC databases. The IRGPs are constructed using immune-related genes (IRGs) with large variations. The least absolute shrinkage and selection operator (LASSO) regression analysis was used to construct IRGPs signature. The IRGPs signature was verified through the ICGC cohort. 1,309 IRGPs were constructed from 90 IRGs with high variability. We obtained 50 IRGPs that were significantly connected to the prognosis and constructed a signature that included 17 IRGPs. In the TCGA and ICGC cohorts, patients were divided into high and low-risk patients by the IRGPs signature. The overall survival time of low-risk patients is longer than that of high-risk patients. After adjustment for clinical and pathological factors, multivariate analysis showed that the IRGPs signature is an independent prognostic factor. The Receiver operating characteristic (ROC) curve confirmed the accuracy of the signature. Besides, gene set enrichment analysis (GSEA) revealed that the signature is related to immune biological processes, and the immune microenvironment status is distinct in different risk patients. The proposed IRGPs signature can effectively assess the overall survival of HCC, and provide the relationship between the signature and the reactivity of immune checkpoint therapy and the sensitivity of targeted drugs, thereby providing new ideas for the diagnosis and treatment of the disease.
Sigma-1 Receptor: A Potential Therapeutic Target for Traumatic Brain Injury
Authors: Shi Mingming , Chen Fanglian , Chen Zhijuan , Yang Weidong , Yue Shuyuan , Zhang Jianning , Chen Xin
Published: October 2021

The sigma-1 receptor (Sig-1R) is a chaperone receptor that primarily resides at the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) and acts as a dynamic pluripotent modulator regulating cellular pathophysiological processes. Multiple pharmacological studies have confirmed the beneficial effects of Sig-1R activation on cellular calcium homeostasis, excitotoxicity modulation, reactive oxygen species (ROS) clearance, and the structural and functional stability of the ER, mitochondria, and MAM. The Sig-1R is expressed broadly in cells of the central nervous system (CNS) and has been reported to be involved in various neurological disorders. Traumatic brain injury (TBI)-induced secondary injury involves complex and interrelated pathophysiological processes such as cellular apoptosis, glutamate excitotoxicity, inflammatory responses, endoplasmic reticulum stress, oxidative stress, and mitochondrial dysfunction. Thus, given the pluripotent modulation of the Sig-1R in diverse neurological disorders, we hypothesized that the Sig-1R may affect a series of pathophysiology after TBI. This review summarizes the current knowledge of the Sig-1R, its mechanistic role in various pathophysiological processes of multiple CNS diseases, and its potential therapeutic role in TBI.
Improvement in Attention Processing After Surgical Treatment in Functional Pituitary Adenomas: Evidence From ERP Study
Authors: Cao Chenglong , Huang Yujing , Chen Aobo , Xu Guozheng , Song Jian
Published: October 2021

Cognitive abilities are impaired in patients with pituitary adenoma. However, studies on attention processing impairment in preoperative patients and attention processing recovery after transsphenoidal adenomectomy are lacking. The study aims to identify the electrophysiological change that relates to attention processing in pituitary patients before and after treatment. Twenty five preoperative pituitary patients and 25 follow-up postoperative patients were recruited. 27 healthy controls (HCs) were matched to the patients with age, gender, and education. Event-related potentials were used to investigate the attention processing in the preoperative patients, postoperative patients, and HCs. Across three groups, all emotional stimuli evoked P200 components. Compared with the HCs or postoperative patients, the amplitudes of P200 in the preoperative patients were higher. Moreover, The amplitudes of P200 decreased in the postoperative patients, which were similar to that in the HCs. The attention processing was improved after surgery, but no significant differences were detected between the postoperative patients and HCs. Abnormal hormone levels may be relevant to the factor that impair attention processing. Compared with that of the HCs and postoperative patients, the P200 component elicited by negative stimuli is higher in preoperative patients, which may illustrate compensatory activity after attention impairments. Furthermore, these data indicate that improvements in attention processing may be attributed to the amelioration of endocrine disorders. This study shows that the P200 component may be used to diagnose attention processing in preoperative pituitary patients and prove the improvement of attention processing in postoperative patients.
Vestibular-Evoked Cerebral Potentials
Authors: Nakul Estelle , Bartolomei Fabrice , Lopez Christophe
Published: October 2021

The human vestibular cortex has mostly been approached using functional magnetic resonance imaging and positron emission tomography combined with artificial stimulation of the vestibular receptors or nerve. Few studies have used electroencephalography and benefited from its high temporal resolution to describe the spatiotemporal dynamics of vestibular information processing from the first milliseconds following vestibular stimulation. Evoked potentials (EPs) are largely used to describe neural processing of other sensory signals, but they remain poorly developed and standardized in vestibular neuroscience and neuro-otology. Yet, vestibular EPs of brainstem, cerebellar, and cortical origin have been reported as early as the 1960s. This review article summarizes and compares results from studies that have used a large range of vestibular stimulation, including natural vestibular stimulation on rotating chairs and motion platforms, as well as artificial vestibular stimulation (e.g., sounds, impulsive acceleration stimulation, galvanic stimulation). These studies identified vestibular EPs with short latency (<20 ms), middle latency (from 20 to 50 ms), and late latency (>50 ms). Analysis of the generators (source analysis) of these responses offers new insights into the neuroimaging of the vestibular system. Generators were consistently found in the parieto-insular and temporo-parietal junction—the core of the vestibular cortex—as well as in the prefrontal and frontal areas, superior parietal, and temporal areas. We discuss the relevance of vestibular EPs for basic research and clinical neuroscience and highlight their limitations.
Safety and Efficacy of the FRED Jr Flow Re-Direction Endoluminal Device for Intracranial Aneurysms: Retrospective Multicenter Experience With Emphasis on Midterm Results
Authors: Jesser Jessica , Alberalar Nilüfer D. , Kizilkilic Osman , Saatci Isil , Baltacioglu Feyyaz , Özlük Enes , Killer-Oberpfalzer Monika , Vollherbst Dominik F. , Islak Civan , Cekirge Saruhan H. , Bendszus Martin , Möhlenbruch Markus , Koçer Naci
Published: October 2021

Background and Purpose: Flow diversion is increasingly used as an endovascular treatment for intracranial aneurysms. In this retrospective multicenter study, we analyzed the safety and efficacy of the treatment of intracranial, unruptured, or previously treated but recanalized aneurysms using Flow Re-Direction Endoluminal Device (FRED) Jr with emphasis on midterm results.

Materials and Methods: Clinical and radiological records of 150 patients harboring 159 aneurysms treated with FRED Jr at six centers between October 2014 and February 2020 were reviewed and consecutively included. Clinical outcome was measured by using the modified Rankin Scale (mRS). Anatomical results were assessed according to the O'Kelly-Marotta (OKM) scale and the Cekirge-Saatci Classification (CSC) scale.

Results: The overall complication rate was 24/159 (16%). Thrombotic-ischemic events occurred in 18/159 treatments (11%). These resulted in long-term neurological sequelae in two patients (1%) with worsening from pre-treatment mRS 0–2 and mRS 4 after treatment. Complete or near-complete occlusion of the treated aneurysm according to the OKM scale was reached in 54% (85/158) at 6-month, in 68% (90/133) at 1-year, and in 83% (77/93) at 2-year follow-up, respectively. The rates of narrowing or occlusion of a vessel branch originating from the treated aneurysm according to the CSC scale were 11% (12/108) at 6-month, 20% (17/87) at 1-year, and 23% (13/57) at 2-year follow-up, respectively, with all cases being asymptomatic.

Conclusions: In this retrospective multicenter study, FRED Jr was safe and effective in the midterm occlusion of cerebral aneurysms. Most importantly, it was associated with a high rate of good clinical outcome.
Consensus Statement on High-Intensity Focused Ultrasound for Functional Neurosurgery in Switzerland
Authors: Stieglitz Lennart H. , Oertel Markus F. , Accolla Ettore A. , Bally Julien , Bauer Roland , Baumann Christian R. , Benninger David , Bohlhalter Stephan , Büchele Fabian , Hägele-Link Stefan , Kägi Georg , Krack Paul , Krüger Marie T. , Mahendran Sujitha , Möller J. Carsten , Mylius Veit , Piroth Tobias , Werner Beat , Kaelin-Lang Alain
Published: October 2021

Background: Magnetic resonance-guided high-intensity focused ultrasound (MRgHiFUS) has evolved into a viable ablative treatment option for functional neurosurgery. However, it is not clear yet, how this new technology should be integrated into current and established clinical practice and a consensus should be found about recommended indications, stereotactic targets, patient selection, and outcome measurements.

Objective: To sum up and unify current knowledge and clinical experience of Swiss neurological and neurosurgical communities regarding MRgHiFUS interventions for brain disorders to be published as a national consensus paper.

Methods: Eighteen experienced neurosurgeons and neurologists practicing in Switzerland in the field of movement disorders and one health physicist representing 15 departments of 12 Swiss clinical centers and 5 medical societies participated in the workshop and contributed to the consensus paper. All experts have experience with current treatment modalities or with MRgHiFUS. They were invited to participate in two workshops and consensus meetings and one online meeting. As part of workshop preparations, a thorough literature review was undertaken and distributed among participants together with a list of relevant discussion topics. Special emphasis was put on current experience and practice, and areas of controversy regarding clinical application of MRgHiFUS for functional neurosurgery.

Results: The recommendations addressed lesioning for treatment of brain disorders in general, and with respect to MRgHiFUS indications, stereotactic targets, treatment alternatives, patient selection and management, standardization of reporting and follow-up, and initialization of a national registry for interventional therapies of movement disorders. Good clinical evidence is presently only available for unilateral thalamic lesioning in treating essential tremor or tremor-dominant Parkinson's disease and, to a minor extent, for unilateral subthalamotomy for Parkinson's disease motor features. However, the workgroup unequivocally recommends further exploration and adaptation of MRgHiFUS-based functional lesioning interventions and confirms the need for outcome-based evaluation of these approaches based on a unified registry. MRgHiFUS and DBS should be evaluated by experts familiar with both methods, as they are mutually complementing therapy options to be appreciated for their distinct advantages and potential.

Conclusion: This multidisciplinary consensus paper is a representative current recommendation for safe implementation and standardized practice of MRgHiFUS treatments for functional neurosurgery in Switzerland.
The Challenging Path to Developing a Mobile Health Device for Epilepsy: The Current Landscape and Where We Go From Here
Authors: Hubbard Ilona , Beniczky Sandor , Ryvlin Philippe
Published: October 2021

Seizure detection, and more recently seizure forecasting, represent important avenues of clinical development in epilepsy, promoted by progress in wearable devices and mobile health (mHealth), which might help optimizing seizure control and prevention of seizure-related mortality and morbidity in persons with epilepsy. Yet, very long-term continuous monitoring of seizure-sensitive biosignals in the ambulatory setting presents a number of challenges. We herein provide an overview of these challenges and current technological landscape of mHealth devices for seizure detection. Specifically, we display, which types of sensor modalities and analytical methods are available, and give insight into current clinical practice guidelines, main outcomes of clinical validation studies, and discuss how to evaluate device performance at point-of-care facilities. We then address pitfalls which may arise in patient compliance and the need to design solutions adapted to user experience.
Arousal State-Dependence of Interactions Between Short- and Long-Term Auditory Novelty Responses in Human Subjects
Authors: Nourski Kirill V. , Steinschneider Mitchell , Rhone Ariane E. , Mueller Rashmi N. , Kawasaki Hiroto , Banks Matthew I.
Published: October 2021

In everyday life, predictable sensory stimuli are generally not ecologically informative. By contrast, novel or unexpected stimuli signal ecologically salient changes in the environment. This idea forms the basis of the predictive coding hypothesis: efficient sensory encoding minimizes neural activity associated with predictable backgrounds and emphasizes detection of changes in the environment. In real life, the brain must resolve multiple unexpected sensory events occurring over different time scales. The local/global deviant experimental paradigm examines auditory predictive coding over multiple time scales. For short-term novelty [hundreds of milliseconds; local deviance (LD)], sequences of identical sounds (/xxxxx/) are interspersed with sequences that contain deviants (/xxxxy/). Long-term novelty [several seconds; global deviance (GD)] is created using either (a) frequent /xxxxx/ and infrequent /xxxxy/ sequences, or (b) frequent /xxxxy/ and infrequent /xxxxx/ sequences. In scenario (a), there is both an LD and a GD effect (LDGD, “double surprise”). In (b), the global deviant is a local standard, i.e., sequence of identical sounds (LSGD). Cortical responses reflecting LD and GD originate in different brain areas, have a different time course, and are differentially sensitive to general anesthesia. Neural processes underlying LD and GD have been shown to interact, reflecting overlapping networks subserving the detection of novel auditory stimuli. This study examined these interactions using intracranial electroencephalography in neurosurgical patients. Subjects performed a GD target detection task before and during induction of anesthesia with propofol. Recordings were made from the auditory cortex, surrounding auditory-related and prefrontal cortex in awake, sedated, and unresponsive states. High gamma activity was used to measure the neural basis of local-by-global novelty interactions. Positive interaction was defined as a greater response to the double surprise LDGD condition compared to LSGD. Negative interaction was defined as a weaker response to LDGD. Positive interaction was more frequent than negative interaction and was primarily found in auditory cortex. Negative interaction typically occurred in prefrontal cortex and was more sensitive to general anesthesia. Temporo-parietal auditory-related areas exhibited both types of interaction. These interactions may have relevance in a clinical setting as biomarkers of conscious perception in the assessment of depth of anesthesia and disorders of consciousness.
Irregular Sleep/Wake Patterns Are Associated With Reduced Quality of Life in Post-treatment Cancer Patients: A Study Across Three Cancer Cohorts
Authors: Trivedi Ritu , Man Hong , Madut Ayey , Mather Marius , Elder Elisabeth , Dhillon Haryana M. , Brand Alison , Howle Julie , Mann Graham , DeFazio Anna , Amis Terence , Cain Sean W. , Phillips Andrew J. K. , Kairaitis Kristina
Published: October 2021

Background: Cancer patients often describe poor sleep quality and sleep disruption as contributors to poor quality of life (QoL). In a cross-sectional study of post-treatment breast, endometrial, and melanoma cancer patients, we used actigraphy to quantify sleep regularity using the sleep regularity index (SRI), and examined relationships with reported sleep symptoms and QoL.

Methods: Participants were recruited post-primary treatment (35 diagnosed with breast cancer, 24 endometrial cancer, and 29 melanoma) and wore an actigraphy device for up to 2 weeks and SRI was calculated. Self-report questionnaires for cancer-related QoL [European Organization for Research and Treatment of Cancer EORTC (QLQ-C30)] were completed. Data were compared using analysis of variance (ANOVA) or Chi-Square tests. Multivariate linear regression analysis was used to determine independent variable predictors for questionnaire-derived data.

Results: Age distribution was similar between cohorts. Endometrial and breast cancer cohorts were predominantly female, as expected, and body mass index (BMI) was higher in the endometrial cancer cohort, followed by breast and melanoma. There were no differences between tumor groups in: total sleep time, sleep onset latency, bedtime, and SRI (breast 80.9 ± 8.0, endometrial 80.3 ± 12.2, and melanoma 81.4 ± 7.0) (all p > 0.05). A higher SRI was associated with both better functional and symptom scores, including increased global QoL, better physical functioning, less sleepiness and fatigue, better sleep quality, and associated with less nausea/vomiting, dyspnea, and diarrhea (all p < 0.05).

Conclusion: In cancer patients post-treatment, greater sleep regularity is associated with increased global QoL, as well as better physical functioning and fewer cancer related symptoms. Improving sleep regularity may improve QoL for cancer patients.
Altered Brain Functional Connectivity at Resting-State in Patients With Non-arteritic Anterior Ischemic Optic Neuropathy
Authors: Zhao Pengbo , Lv Han , Guo Pengde , Su Yan , Liu Ming , Wang Yan , Hua Haiqin , Kang Shaohong
Published: October 2021

Purpose:To investigate the possible changes in functional connectivity (FC) in patients with non-arteritic anterior ischemic optic neuropathy (NAION) using resting-state functional MRI (fMRI).

Methods:Thirty-one NAION patients and 31 healthy controls were recruited and underwent resting-state fMRI scans. Regions of interest (ROIs) were defined as bilateral Brodmann’s area 17 (BA17). FC analysis was performed between the ROIs and the rest of the brain regions, and the between group comparisons of FC were performed. We conducted correlation analysis between the FC changes and the clinical variables in NAION patients.

Results:Compared with healthy controls, patients with NAION showed significantly decreased FC between the left BA17 and the right inferior frontal gyrus, left caudate nucleus. As for the right BA17, patients exhibited significantly increased FC with the left olfactory gyrus and decreased FC with the right superior frontal gyrus (SFG), right insula. Moreover, FC values between the right insula and the right BA17 were positively correlated with the right side of mean sensitivity in the central visual field (r= 0.52,P< 0.01) and negatively correlated with the right side of mean defect in the central visual field (r= −0.55,P< 0.01).

Conclusion:Our study indicated that patients with NAION showed significantly abnormal functional reorganization between the primary visual cortex and several other brain regions not directly related to visual function, which supports that NAION may not only be an ophthalmic disease but also a neuro-ophthalmological disease.
Indoles Derived From Glucobrassicin: Cancer Chemoprevention by Indole-3-Carbinol and 3,3'-Diindolylmethane
Authors: Williams David E.
Published: October 2021

Hydrolysis of glucobrassicin by plant or bacterial myrosinase produces multiple indoles predominantly indole-3-carbinol (I3C). I3C and its majorin vivoproduct, 3,3'-diindolylmethane (DIM), are effective cancer chemopreventive agents in pre-clinical models and show promise in clinical trials. The pharmacokinetics/pharmacodynamics of DIM have been studied in both rodents and humans and urinary DIM is a proposed biomarker of dietary intake of cruciferous vegetables. Recent clinical studies at Oregon State University show surprisingly robust metabolism of DIMin vivowith mono- and di-hydroxylation followed by conjugation with sulfate or glucuronic acid. DIM has multiple mechanisms of action, the most well-characterized is modulation of aryl hydrocarbon receptor (AHR) signaling. In rainbow trout dose-dependent cancer chemoprevention by dietary I3C is achieved when given prior to or concurrent with aflatoxin B1, polycyclic aromatic hydrocarbons, nitrosamines or direct acting carcinogens such as N-methyl-N'-nitro-nitrosoguanidine. Feeding pregnant mice I3C inhibits transplacental carcinogenesis. In humans much of the focus has been on chemoprevention of breast and prostate cancer. Alteration of cytochrome P450-dependent estrogen metabolism is hypothesized to be an important driver of DIM-dependent breast cancer prevention. The few studies done to date comparing glucobrassicin-rich crucifers such as Brussels sprouts with I3C/DIM supplements have shown the greater impact of the latter is due to dose. Daily ingestion of kg quantities of Brussels sprouts is required to producein vivolevels of DIM achievable by supplementation. In clinical trials these supplement doses have elicited few if any adverse effects. Sulforaphane from glucoraphanin can act synergistically with glucobrassicin-derived DIM and this may lead to opportunities for combinatorial approaches (supplement and food-based) in the clinic.
Use of Machine Learning and Statistical Algorithms to Predict Hospital Length of Stay Following Colorectal Cancer Resection: A South African Pilot Study
Authors: Achilonu Okechinyere J. , Fabian June , Bebington Brendan , Singh Elvira , Nimako Gideon , Eijkemans Rene M. J. C. , Musenge Eustasius
Published: October 2021

The aim of this pilot study was to develop logistic regression (LR) and support vector machine (SVM) models that differentiate low from high risk for prolonged hospital length of stay (LOS) in a South African cohort of 383 colorectal cancer patients who underwent surgical resection with curative intent. Additionally, the impact of 10-fold cross-validation (CV), Monte Carlo CV, and bootstrap internal validation methods on the performance of the two models was evaluated. The median LOS was 9 days, and prolonged LOS was defined as greater than 9 days post-operation. Preoperative factors associated with prolonged LOS were a prior history of hypertension and an Eastern Cooperative Oncology Group score between 2 and 4. Postoperative factors related to prolonged LOS were the need for a stoma as part of the surgical procedure and the development of post-surgical complications. The risk of prolonged LOS was higher in male patients and in any patient with lower preoperative hemoglobin. The highest area under the receiving operating characteristics (AU-ROC) was achieved using LR of 0.823 (CI = 0.798–0.849) and SVM of 0.821 (CI = 0.776–0.825), with each model using the Monte Carlo CV method for internal validation. However, bootstrapping resulted in models with slightly lower variability. We found no significant difference between the models across the three internal validation methods. The LR and SVM algorithms used in this study required incorporating important features for optimal hospital LOS predictions. The factors identified in this study, especially postoperative complications, can be employed as a simple and quick test clinicians may flag a patient at risk of prolonged LOS.
A Multi-Institutional Analysis of Prostate Cancer Patients With or Without 68Ga-PSMA PET/CT Prior to Salvage Radiotherapy of the Prostatic Fossa
Authors: Schmidt-Hegemann Nina-Sophie , Zamboglou Constantinos , Thamm Reinhard , Eze Chukwuka , Kirste Simon , Spohn Simon , Li Minglun , Stief Christian , Bolenz Christian , Schultze-Seemann Wolfgang , Bartenstein Peter , Prasad Vikas , Ganswindt Ute , Grosu Anca-Ligia , Belka Claus , Mayer Benjamin , Wiegel Thomas
Published: October 2021

Introduction

68Ga-PSMA PET/CT is associated with unprecedented sensitivity for localization of biochemically recurrent prostate cancer at low PSA levels prior to radiotherapy. Aim of the present analysis is to examine whether patients undergoing postoperative, salvage radiotherapy (sRT) of the prostatic fossa with no known nodal or distant metastases on conventional imaging (CT and/or MRI) and on positron emission tomography/computed tomography (68Ga-PSMA PET/CT) will have an improved biochemical recurrence-free survival (BRFS) compared to patients with no known nodal or distant metastases on conventional imaging only.

Material and Methods

This retrospective analysis is based on 459 patients (95 with and 364 without 68Ga-PSMA PET/CT). BRFS (PSA < post-sRT Nadir + 0.2 ng/ml) was the primary study endpoint. This was first analysed by Kaplan-Meier and uni- and multivariate Cox regression analysis for the entire cohort and then again after matched-pair analysis using tumor stage, Gleason score, PSA at time of sRT and radiation dose as matching parameters.

Results

Median follow-up was 77.5 months for patients without and 33 months for patients with 68Ga-PSMA PET/CT. For the entire cohort, tumor stage (pT2 vs. pT3-4; p= <0.001), Gleason score (GS ≤ 7 vs. GS8-10; p=0.003), pre-sRT PSA (<0.5 vs. ≥0.5ng/ml; p<0.001) and sRT dose (<70 vs. ≥70Gy; p<0.001) were the only factors significantly associated with improved BRFS. This was not seen for the use of 68Ga-PSMA PET/CT prior to sRT (p=0.789). Matched-pair analysis consisted of 95 pairs of PCa patients with or without PET/CT and no significant difference in BRFS based on the use of PET/CT was evident (p=0.884).

Conclusion

This analysis did not show an improvement in BRFS using 68Ga-PSMA PET/CT prior to sRT neither for the entire cohort nor after matched-pair analysis after excluding patients with PET-positive lymph node or distant metastases a priori. As no improved BRFS resulted with implementation of 68Ga-PSMA PET in sRT planning, sRT should not be deferred until the best “diagnostic window” for 68Ga-PSMA PET/CT.
Do We Need Intraoperative Magnetic Resonance Imaging in All Endoscopic Endonasal Pituitary Adenoma Surgery Cases? A Retrospective Study
Authors: Celtikci Emrah , Sahin Muammer Melih , Sahin Mustafa Caglar , Cindil Emetullah , Demirtaş Zuhal , Emmez Hakan
Published: October 2021

There are previous reports investigating effectiveness of intraoperative magnetic resonance imaging (IO-MRI) in pituitary adenoma surgery but there is no clear data in the literature recommending when there is no need of intraoperative scan. This retrospective analysis was based on determining which patients does not need any IO-MRI scan following endoscopic endonasal pituitary adenoma surgery. Patients with functional or non-functional pituitary adenomas that were operated via endoscopic endonasal approach (EEA) between June 2017 and May 2019 were enrolled. Patients younger than 18 years old, patients who did not underwent IO-MRI procedure or not operated via EEA were excluded from the study. Hence, this study is designed to clarify if IO-MRI is useful in both functional and non-functional pituitary adenomas, functional adenomas did not split into subgroups. A total of 200 patients treated with pituitary adenoma were included. In Knosp Grade 0 – 2 group, primary surgeon’s opinion and IO-MRI findings were compatible in 150 patients (98.6%). In Knosp Grade 3 – 4 correct prediction were performed in 32 (66.6%) patients. When incorrectly predicted Knosp Grade 3 – 4 patients (n = 16) was analyzed, in 13 patients there were still residual tumor in cavernous sinus and in 3 patients there were no residual tumor. Fisher’s exact test showed there is a statistically significant difference of correct prediction between two different Knosp Grade groups (two-tailed P < 0.0001). Eighteen patients had a residual tumor extending to the suprasellar and parasellar regions which second most common site for residual tumor. Our findings demonstrate that there is no need of IO-MRI scan while operating adenomas limited in the sellae and not invading the cavernous sinus. However, we strongly recommend IO-MRI if there is any suprasellar and parasellar extension and/or cavernous sinus invasion.
Expression Levels of Three Key Genes CCNB1, CDC20, and CENPF in HCC Are Associated With Antitumor Immunity
Authors: Si Tengfei , Huang Zhenlin , Jiang Yuanhang , Walker-Jacobs Abigail , Gill Shaqira , Hegarty Robert , Hamza Mohammad , Khorsandi Shirin Elizabeth , Jassem Wayel , Heaton Nigel , Ma Yun
Published: October 2021

Introduction

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a low 5-year survival rate. The heterogeneity of HCC makes monotherapy unlikely. The development of diagnostic programs and new treatments targeting common genetic events in the carcinogenic process are providing further insights into the management of HCC. The aim of this study was firstly to validate key genes that are involved in promoting HCC development and as biomarkers for early diagnosis and, secondly, to define their links with antitumor immunity including inhibitory checkpoints.

Methods

Multiple databases including Gene Expression Omnibus (GEO), Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan–Meier Plotter, UALCAN, and Oncomine were used for target gene screening and establishment of a co-expression network. Clinical data and RNAseq of 367 HCC patients were downloaded from the Cancer Genome Atlas (TCGA) database. The diagnostic and prognostic value of screened genes were tested by receiver operating characteristic (ROC) curve and correlation analysis. The links with the key genes in HCC and antitumor immunity were defined using both blood and liver tissue collected prospectively from HCC patients in our center.

Results

Upregulation of CCNB1, CDC20, and CENPF was commonly observed in HCC and are involved in the p53 signal pathway. The hepatic mRNA expression levels of these three genes were strongly associated with patients’ prognosis and expressed high value of area under the ROC curve (AUC). Further analysis revealed that these three genes were positively correlated with the gene expression levels of IFN-γ, TNF-α, and IL-17 in peripheral blood. In addition, the expression of CENPF showed positive correlation with the percentage of CD8pos T cells and negative correlation with the percentage of CD4pos T cells in the peripheral blood. In the HCC microenvironment, the transcript levels of these three genes and inhibitory checkpoint molecules including PD-1, CTLA-4, and TIM-3 were positively correlated.

Conclusion

The upregulation of CCNB1, CDC20, and CENPF genes was a common event in hepatocarcinogenesis. Expression levels of CCNB1, CDC20, and CENPF showed potential for early diagnosis and prediction of prognosis in HCC patients. There is a close association between three genes and Th1/Th17 cytokines as well as the count of CD4pos and CD8pos T cells. The positive correlation between the three genes and inhibitory checkpoint genes, PD-1, CTLA-4, and TIM-3, indicates that these genes are linked with weakened antitumor immunity in HCC. Our findings may provide further insights into developing novel therapies for HCC.
First-In-Human Study in Cancer Patients Establishing the Feasibility of Oxygen Measurements in Tumors Using Electron Paramagnetic Resonance With the OxyChip
Authors: Schaner Philip E. , Williams Benjamin B. , Chen Eunice Y. , Pettus Jason R. , Schreiber Wilson A. , Kmiec Maciej M. , Jarvis Lesley A. , Pastel David A. , Zuurbier Rebecca A. , DiFlorio-Alexander Roberta M. , Paydarfar Joseph A. , Gosselin Benoit J. , Barth Richard J. , Rosenkranz Kari M. , Petryakov Sergey V. , Hou Huagang , Tse Dan , Pletnev Alexandre , Flood Ann Barry , Wood Victoria A. , Hebert Kendra A. , Mosher Robyn E. , Demidenko Eugene , Swartz Harold M. , Kuppusamy Periannan
Published: October 2021

Objective

The overall objective of this clinical study was to validate an implantable oxygen sensor, called the ‘OxyChip’, as a clinically feasible technology that would allow individualized tumor-oxygen assessments in cancer patients prior to and during hypoxia-modification interventions such as hyperoxygen breathing.

Methods

Patients with any solid tumor at ≤3-cm depth from the skin-surface scheduled to undergo surgical resection (with or without neoadjuvant therapy) were considered eligible for the study. The OxyChip was implanted in the tumor and subsequently removed during standard-of-care surgery. Partial pressure of oxygen (pO2) at the implant location was assessed using electron paramagnetic resonance (EPR) oximetry.

Results

Twenty-three cancer patients underwent OxyChip implantation in their tumors. Six patients received neoadjuvant therapy while the OxyChip was implanted. Median implant duration was 30 days (range 4–128 days). Forty-five successful oxygen measurements were made in 15 patients. Baseline pO2 values were variable with overall median 15.7 mmHg (range 0.6–73.1 mmHg); 33% of the values were below 10 mmHg. After hyperoxygenation, the overall median pO2 was 31.8 mmHg (range 1.5–144.6 mmHg). In 83% of the measurements, there was a statistically significant (p ≤ 0.05) response to hyperoxygenation.

Conclusions

Measurement of baseline pO2 and response to hyperoxygenation using EPR oximetry with the OxyChip is clinically feasible in a variety of tumor types. Tumor oxygen at baseline differed significantly among patients. Although most tumors responded to a hyperoxygenation intervention, some were non-responders. These data demonstrated the need for individualized assessment of tumor oxygenation in the context of planned hyperoxygenation interventions to optimize clinical outcomes.
Large Granular Lymphocyte Expansion in Myeloid Diseases and Bone Marrow Failure Syndromes: Whoever Seeks Finds
Authors: Fattizzo Bruno , Bellani Valentina , Pasquale Raffaella , Giannotta Juri Alessandro , Barcellini Wilma
Published: October 2021

Large granular lymphocytes (LGL) are lymphoid cells characterized by either a T-cell or a natural killer phenotype whose expansion may be reactive to toxic, infectious, and neoplastic conditions, or result from clonal selection. Recently, the higher attention to LGL clones led to their detection in many clinical conditions including myeloid neoplasms and bone marrow failures. In these contexts, it is still unclear whether LGL cells actively contribute to anti-stem cell autoimmunity or are only a reaction to dysplastic/leukemic myelopoiesis. Moreover, some evidence exists about a common clonal origin of LGL and myeloid clones, including the detection of STAT3 mutations, typical of LGL, in myeloid precursors from myelodysplastic patients. In this article we reviewed available literature regarding the association of LGL clones with myeloid neoplasms (myelodysplastic syndromes, myeloproliferative neoplasms, and acute myeloid leukemias) and bone marrow failures (aplastic anemia and pure red cell aplasia, PRCA) focusing on evidence of pathogenic, clinical, and prognostic relevance. It emerged that LGL clones may be found in up to one third of patients, particularly those with PRCA, and are associated with a more cytopenic phenotype and good response to immunosuppression. Pathogenically, LGL clones seem to expand after myeloid therapies, whilst immunosuppression leading to LGL depletion may favor leukemic escape and thus requires caution.
Identification of CDCA2 as a Diagnostic and Prognostic Marker for Hepatocellular Carcinoma
Authors: Yu Zhenjun , Zhang Yu , Shao Shuai , Liu Qi , Li Yuhan , Du Xiaoxiao , Zhang Kun , Zhang Mengxia , Yuan Haixia , Yuan Qiang , Liu Tong , Gao Yingtang , Wang Yijun , Hong Wei , Han Tao
Published: October 2021

Objective

Hepatocellular carcinoma (HCC) is one of the most common and malignant tumors with an insidious onset, difficult early diagnosis, and limited therapy options, resulting in a poor prognosis. Cell division cycle associated 2 (CDCA2), also known as Repo-Man, plays an important role in regulating mitosis and DNA repair, but the involvement of CDCA2 in HCC remains unclear.

Methods

The differentially expressed genes that were significantly upregulated in multiple RNA sequencing datasets of HCC were screened. Receiver operating characteristic (ROC) curve analysis was performed to identify diagnostic markers for HCC. Least absolute shrinkage and selection operator Cox regression analysis was performed to screen the prognosis-related genes. The screening and analyses identified CDCA2 as the target gene in this study. The expression of CDCA2 was analyzed in public databases and clinical specimens, and CDCA2 involvement in HCC was explored by both bioinformatic analysis and in vitro experiments.

Results

The level of CDCA2 was enhanced in HCC compared with healthy livers. Overexpression of CDCA2 positively correlated with the pathological grade and TNM stage of the diseases. Furthermore, CDCA2 was found to be an independent prognostic predictor. An excellent prognostic model of HCC was successfully constructed with CDCA2 in combination with TNM stage. Bioinformatic analysis revealed that CDCA2 was closely associated with the cell cycle, apoptosis, and p53 signaling pathway. Silencing CDCA2 in Huh7 cells resulted in significant upregulation of p53 and the downstream PUMA and NOXA and a subsequently increased apoptosis. Inhibition of p53 signaling and apoptosis was found after overexpression of CDCA2 in L02 cells. Strikingly, the proliferation of cells was not affected by CDCA2.

Conclusions

CDCA2 was a novel diagnostic marker for HCC, and overexpression of this gene reflected poor pathological grade, stage, and clinical prognosis. CDCA2 promoted the pathogenesis of HCC by suppressing the p53-PUMA/NOXA signaling and the subsequent apoptosis.