bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Epidemiology of Carbapenem-Resistant Acinetobacter baumannii From Khartoum State, Sudan
Authors: Al-Hassan Leena , Elbadawi Hana , Osman Einas , Ali Sara , Elhag Kamal , Cantillon Daire , Wille Julia , Seifert Harald , Higgins Paul G.
Published: February 2021

Carbapenem resistant Acinetobacter baumannii (CRAb) is an important global pathogen contributing to increased morbidity and mortality in hospitalized patients, due to limited alternative treatment options. Nine international clonal (IC) lineages have been identified in many countries worldwide, however, data still lacks from some parts of the world, particularly in Africa. We hereby present the molecular epidemiology of MDR A. baumannii from four hospitals in Khartoum, Sudan, collected from 2017 to 2018. Forty-two isolates were whole-genome sequenced, and subsequent molecular epidemiology was determined by core genome MLST (cgMLST), and their resistomes identified. All isolates had an array of diverse antibiotic resistance mechanisms conferring resistance to multiple classes of antibiotics. We found a predominance (88%) of IC2 (with the intrinsic OXA-66 and acquired OXA-23), and some with NDM-1. IC2 isolates were sub-divided into 4 STs separated by 5 to 431 allelic differences, and with evidence of seven transmission clusters. Isolates belonging to IC1, IC5, and IC9 were also identified. These data illustrate that MDR IC2 A. baumannii are widely distributed in Khartoum hospitals and are in possession of multiple antibiotic resistance determinants.
Low Bifidobacterium Abundance in the Lower Gut Microbiota Is Associated With Helicobacter pylori-Related Gastric Ulcer and Gastric Cancer
Authors: Devi T. Barani , Devadas Krishnadas , George Meekha , Gandhimathi A. , Chouhan Deepak , Retnakumar R. J. , Alexander Sneha Mary , Varghese Jijo , Dharmaseelan Sanjai , Chandrika Sivakumar Krishnankutty , Jissa V. T. , Das Bhabatosh , Nair G. Balakrish , Chattopadhyay Santanu
Published: February 2021

Helicobacter pylori infection in stomach leads to gastric cancer, gastric ulcer, and duodenal ulcer. More than 1 million people die each year due to these diseases, but why most H. pylori-infected individuals remain asymptomatic while a certain proportion develops such severe gastric diseases remained an enigma. Several studies indicated that gastric and intestinal microbiota may play a critical role in the development of the H. pylori-associated diseases. However, no specific microbe in the gastric or intestinal microbiota has been clearly linked to H. pylori infection and related gastric diseases. Here, we studied H. pylori infection, its virulence genes, the intestinal microbiota, and the clinical status of Trivandrum residents (N = 375) in southwestern India by standard H. pylori culture, PCR genotype, Sanger sequencing, and microbiome analyses using Illumina Miseq and Nanopore GridION. Our analyses revealed that gastric colonization by virulent H. pylori strains (vacAs1i1m1cagA+) is necessary but not sufficient for developing these diseases. Conversely, distinct microbial pools exist in the lower gut of the H. pylori-infected vs. H. pylori-non-infected individuals. Bifidobacterium (belonging to the phylum Actinobacteria) and Bacteroides (belonging to the phylum Bacteroidetes) were present in lower relative abundance for the H. pylori+ group than the H. pylori- group (p < 0.05). On the contrary, for the H. pylori+ group, genus Dialister (bacteria belonging to the phylum Firmicutes) and genus Prevotella (bacteria belonging to the phylum Bacteroidetes) were present in higher abundance compared to the H. pylori- group (p < 0.05). Notably, those who carried H. pylori in the stomach and had developed aggressive gastric diseases also had extremely low relative abundance (p < 0.05) of several Bifidobacterium species (e.g., B. adolescentis, B. longum) in the lower gut suggesting a protective role of Bifidobacterium. Our results show the link between lower gastrointestinal microbes and upper gastrointestinal diseases. Moreover, the results are important for developing effective probiotic and early prognosis of severe gastric diseases.
Drug Repurposing Strategy (DRS): Emerging Approach to Identify Potential Therapeutics for Treatment of Novel Coronavirus Infection
Authors: Sahoo Biswa Mohan , Ravi Kumar B. V. V. , Sruti J. , Mahapatra Manoj Kumar , Banik Bimal K. , Borah Preetismita
Published: February 2021

Drug repurposing is also termed as drug repositioning or therapeutic switching. This method is applied to identify the novel therapeutic agents from the existing FDA approved clinically used drug molecules. It is considered as an efficient approach to develop drug candidates with new pharmacological activities or therapeutic properties. As the drug discovery is a costly, time-consuming, laborious, and highly risk process, the novel approach of drug repositioning is employed to increases the success rate of drug development. This strategy is more advantageous over traditional drug discovery process in terms of reducing duration of drug development, low-cost, highly efficient and minimum risk of failure. In addition to this, World health organization declared Coronavirus disease (COVID-19) as pandemic globally on February 11, 2020. Currently, there is an urgent need to develop suitable therapeutic agents for the prevention of the outbreak of COVID-19. So, various investigations were carried out to design novel drug molecules by utilizing different approaches of drug repurposing to identify drug substances for treatment of COVID-19, which can act as significant inhibitors against viral proteins. It has been reported that COVID-19 can infect human respiratory system by entering into the alveoli of lung via respiratory tract. So, the infection occurs due to specific interaction or binding of spike protein with angiotensin converting enzyme-2 (ACE-2) receptor. Hence, drug repurposing strategy is utilized to identify suitable drugs by virtual screening of drug libraries. This approach helps to determine the binding interaction of drug candidates with target protein of coronavirus by using computational tools such as molecular similarity and homology modeling etc. For predicting the drug-receptor interactions and binding affinity, molecular docking study and binding free energy calculations are also performed. The methodologies involved in drug repurposing can be categorized into three groups such as drug-oriented, target-oriented and disease or therapy-oriented depending on the information available related to quality and quantity of the physico-chemical, biological, pharmacological, toxicological and pharmacokinetic property of drug molecules. This review focuses on drug repurposing strategy applied for existing drugs including Remdesivir, Favipiravir, Ribavirin, Baraticinib, Tocilizumab, Chloroquine, Hydroxychloroquine, Prulifloxacin, Carfilzomib, Bictegravir, Nelfinavir, Tegobuvir and Glucocorticoids etc to determine their effectiveness toward the treatment of COVID-19.
Target Detection Using Ternary Classification During a Rapid Serial Visual Presentation Task Using Magnetoencephalography Data
Authors: Zhang Chuncheng , Qiu Shuang , Wang Shengpei , He Huiguang
Published: February 2021

Background: The rapid serial visual presentation (RSVP) paradigm is a high-speed paradigm of brain–computer interface (BCI) applications. The target stimuli evoke event-related potential (ERP) activity of odd-ball effect, which can be used to detect the onsets of targets. Thus, the neural control can be produced by identifying the target stimulus. However, the ERPs in single trials vary in latency and length, which makes it difficult to accurately discriminate the targets against their neighbors, the near-non-targets. Thus, it reduces the efficiency of the BCI paradigm.

Methods: To overcome the difficulty of ERP detection against their neighbors, we proposed a simple but novel ternary classification method to train the classifiers. The new method not only distinguished the target against all other samples but also further separated the target, near-non-target, and other, far-non-target samples. To verify the efficiency of the new method, we performed the RSVP experiment. The natural scene pictures with or without pedestrians were used; the ones with pedestrians were used as targets. Magnetoencephalography (MEG) data of 10 subjects were acquired during presentation. The SVM and CNN in EEGNet architecture classifiers were used to detect the onsets of target.

Results: We obtained fairly high target detection scores using SVM and EEGNet classifiers based on MEG data. The proposed ternary classification method showed that the near-non-target samples can be discriminated from others, and the separation significantly increased the ERP detection scores in the EEGNet classifier. Moreover, the visualization of the new method suggested the different underling of SVM and EEGNet classifiers in ERP detection of the RSVP experiment.

Conclusion: In the RSVP experiment, the near-non-target samples contain separable ERP activity. The ERP detection scores can be increased using classifiers of the EEGNet model, by separating the non-target into near- and far-targets based on their delay against targets.
Cognitive Functioning of Glucocerebrosidase (GBA) Non-manifesting Carriers
Authors: Moran Eileen E. , Bressman Susan B. , Ortega Roberto A. , Raymond Deborah , Nichols William C. , Palmese Christina A. , Elango Sonya , Swan Matthew , Shanker Vicki , Perera Imali , Wang Cuiling , Zimmerman Molly E. , Saunders-Pullman Rachel
Published: February 2021

Mutations and variants in the glucocerebrosidase (GBA) gene are among the most common genetic risk factors for the development of Parkinson's disease (PD). Yet, penetrance is markedly reduced, and less is known about the burden of carrying a single mutation among those without diagnosed PD. Motor, cognitive, psychiatric, and olfactory functioning were assessed in 30 heterozygous GBA mutation carriers without PD (the majority of whom had mild GBA mutations) and 49 non-carriers without PD. Study focus was on domains affected in GBA mutation carriers with PD, as well as those previously shown to be abnormal in GBA mutation carriers without PD. GBA mutation carriers showed poorer performance on the Stroop interference measure of executive functioning when controlling for age. There were no group differences in verbal memory, Montreal Cognitive Assessment (MoCA), overall motor score, or presence of REM sleep behavior disorder or depression. Although total olfaction scores did not differ, GBA mutation carriers with hyposmia had lower global cognition scores than those without hyposmia. As anticipated by the low penetrance of GBA mutations, these findings suggest that pre-manifest non-motor or motor features of PD may not present in most GBA mutation carriers. However, there is support that there may be a subtle difference in executive functioning among some non-manifesting heterozygous GBA mutation carriers, and, combined with olfaction, this may warrant additional scrutiny as a potential biomarker for pre-manifest and pre-clinical GBA related PD.
Language Familiarity and Proficiency Leads to Differential Cortical Processing During Translation Between Distantly Related Languages
Authors: Shinozuka Katsumasa , Niioka Kiyomitsu , Tokuda Tatsuya , Kyutoku Yasushi , Okuno Koki , Takahashi Tomoki , Dan Ippeita
Published: February 2021

In the midst of globalization, English is regarded as an international language, or Lingua Franca, but learning it as a second language (L2) remains still difficult to speakers of other languages. This is true especially for the speakers of languages distantly related to English such as Japanese. In this sense, exploring neural basis for translation between the first language (L1) and L2 is of great interest. There have been relatively many previous researches revealing brain activation patterns during translations between L1 and English as L2. These studies, which focused on language translation with close or moderate linguistic distance (LD), have suggested that the Broca area (BA 44/45) and the dorsolateral prefrontal cortex (DLPFC; BA 46) may play an important role on translation. However, the neural mechanism of language translation between Japanese and English, having large LD, has not been clarified. Thus, we used functional near infrared spectroscopy (fNIRS) to investigate the brain activation patterns during word translation between Japanese and English. We also assessed the effects of translation directions and word familiarity. All participants’ first language was Japanese and they were learning English. Their English proficiency was advanced or elementary. We selected English and Japanese words as stimuli based on the familiarity for Japanese people. Our results showed that the brain activation patterns during word translation largely differed depending on their English proficiency. The advanced group elicited greater activation on the left prefrontal cortex around the Broca’s area while translating words with low familiarity, but no activation was observed while translating words with high familiarity. On the other hand, the elementary group evoked greater activation on the left temporal area including the superior temporal gyrus (STG) irrespective of the word familiarity. These results suggested that different cognitive process could be involved in word translation corresponding to English proficiency in Japanese learners of English. These difference on the brain activation patterns between the advanced and elementary group may reflect the difference on the cognitive loads depending on the levels of automatization in one’s language processing.
Long-Term Mutual Training for the CYBATHLON BCI Race With a Tetraplegic Pilot: A Case Study on Inter-Session Transfer and Intra-Session Adaptation
Authors: Hehenberger Lea , Kobler Reinmar J. , Lopes-Dias Catarina , Srisrisawang Nitikorn , Tumfart Peter , Uroko John B. , Torke Paul R. , Müller-Putz Gernot R.
Published: February 2021

CYBATHLON is an international championship where people with severe physical disabilities compete with the aid of state-of-the-art assistive technology. In one of the disciplines, the BCI Race, tetraplegic pilots compete in a computer game race by controlling an avatar with a brain-computer interface (BCI). This competition offers a perfect opportunity for BCI researchers to study long-term training effects in potential end-users, and to evaluate BCI performance in a realistic environment. In this work, we describe the BCI system designed by the team Mirage91 for participation in the CYBATHLON BCI Series 2019, as well as in the CYBATHLON 2020 Global Edition. Furthermore, we present the BCI’s interface with the game and the main methodological strategies, along with a detailed evaluation of its performance over the course of the training period, which lasted 14 months. The developed system was a 4-class BCI relying on task-specific modulations of brain rhythms. We implemented inter-session transfer learning to reduce calibration time, and to reinforce the stability of the brain patterns. Additionally, in order to compensate for potential intra-session shifts in the features’ distribution, normalization parameters were continuously adapted in an unsupervised fashion. Across the aforementioned 14 months, we recorded 26 game-based training sessions. Between the first eight sessions, and the final eight sessions leading up to the CYBATHLON 2020 Global Edition, the runtimes significantly improved from 255 ± 23 s (mean ± std) to 225 ± 22 s, respectively. Moreover, we observed a significant increase in the classifier’s accuracy from 46 to 53%, driven by more distinguishable brain patterns. Compared to conventional single session, non-adaptive BCIs, the inter-session transfer learning and unsupervised intra-session adaptation techniques significantly improved the performance. This long-term study demonstrates that regular training helped the pilot to significantly increase the distance between task-specific patterns, which resulted in an improvement of performance, both with respect to class separability in the calibration data, and with respect to the game. Furthermore, it shows that our methodological approaches were beneficial in transferring the performance across sessions, and most importantly to the CYBATHLON competitions.
Novel Neuroimaging Biomarker for Sleep Quality in Insomnia Disorder: A Hypothalamus Resting State Study
Authors: Ding Shuang , Gao Lijuan , Kukun Hanjiaerbieke , Ai Kai , Zhao Wei , Xie Chao , Wang Yunling
Published: February 2021

Despite striking progress in the understanding of the neurobiology of insomnia disorder (ID), about 40% of ID patients do not reach sustained remission with the primary treatments. It is necessary to reveal novel neuroimaging biomarkers for sleep quality in ID. The hypothalamus has a central role in sleep-wake regulation by communicating with different brain regions. However, the functional implications of hypothalamus circuitry with other brain areas remains largely unknown in ID. It may be speculated that dysfunctional circuitry in the hypothalamus is involved in the pathogenesis of ID. Thus, we investigated the different network organizations of the bilateral hypothalamus during the resting-state between 26 ID patients and 28 healthy controls (HC). Correlation analysis has been carried out to link the neuroimaging findings and Pittsburgh sleep quality index (PSQI) scores. Group comparisons reveal that the resting-state functional connectivity (RSFC) between the left hypothalamic region and a few other brain regions, including the medial prefrontal cortex (mPFC) and pallidum, are significantly higher in ID compared with HC. The right inferior temporal cortex showed reduced RSFC with the left hypothalamus. No significantly different RSFC between ID and HC was detected for the right hypothalamus. Positive correlations with PSQI scores were observed for RSFC strength between the left hypothalamus and bilateral mPFC (left: r = 0.2985, p = 0.0393; right: r = 0.3723, p = 0.0056). Similarly, the RSFC strength between the right hypothalamus and bilateral mPFC (left: r = 0.3980, p = 0.0029; right: r = 0.2972, p = 0.0291) also showed significant positive correlations with PSQI scores. In conclusion, we reveal a novel neuroimaging biomarker for sleep quality, i.e., the RSFC strength of the hypothalamus-mPFC pathway. Consistent with the hyperarousal model of ID, our results shed new insights into the implications of the hyper-connection within hypothalamus circuits in the pathology of the ID.
Oxidative Stress, Inflammation, and Autophagy: Potential Targets of Mesenchymal Stem Cells-Based Therapies in Ischemic Stroke
Authors: He Jialin , Liu Jianyang , Huang Yan , Tang Xiangqi , Xiao Han , Hu Zhiping
Published: February 2021

Ischemic stroke is a leading cause of death worldwide; currently available treatment approaches for ischemic stroke are to restore blood flow, which reduce disability but are time limited. The interruption of blood flow in ischemic stroke contributes to intricate pathophysiological processes. Oxidative stress and inflammatory activity are two early events in the cascade of cerebral ischemic injury. These two factors are reciprocal causation and directly trigger the development of autophagy. Appropriate autophagy activity contributes to brain recovery by reducing oxidative stress and inflammatory activity, while autophagy dysfunction aggravates cerebral injury. Abundant evidence demonstrates the beneficial impact of mesenchymal stem cells (MSCs) and secretome on cerebral ischemic injury. MSCs reduce oxidative stress through suppressing reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation and transferring healthy mitochondria to damaged cells. Meanwhile, MSCs exert anti-inflammation properties by the production of cytokines and extracellular vesicles, inhibiting proinflammatory cytokines and inflammatory cells activation, suppressing pyroptosis, and alleviating blood–brain barrier leakage. Additionally, MSCs regulation of autophagy imbalances gives rise to neuroprotection against cerebral ischemic injury. Altogether, MSCs have been a promising candidate for the treatment of ischemic stroke due to their pleiotropic effect.
Stimulation in the Rat Anterior Insula and Anterior Cingulate During an Effortful Weightlifting Task
Authors: Silva Carlos , Porter Blake S. , Hillman Kristin L.
Published: February 2021

When performing tasks, animals must continually assess how much effort is being expended, and gage this against ever-changing physiological states. As effort costs mount, persisting in the task may be unwise. The anterior cingulate cortex (ACC) and the anterior insular cortex are implicated in this process of cost-benefit decision-making, yet their precise contributions toward driving effortful persistence are not well understood. Here we investigated whether electrical stimulation of the ACC or insular cortex would alter effortful persistence in a novel weightlifting task (WLT). In the WLT an animal is challenged to pull a rope 30 cm to trigger food reward dispensing. To make the action increasingly effortful, 45 g of weight is progressively added to the rope after every 10 successful pulls. The animal can quit the task at any point – with the rope weight at the time of quitting taken as the “break weight.” Ten male Sprague-Dawley rats were implanted with stimulating electrodes in either the ACC [cingulate cortex area 1 (Cg1) in rodent] or anterior insula and then assessed in the WLT during stimulation. Low-frequency (10 Hz), high-frequency (130 Hz), and sham stimulations were performed. We predicted that low-frequency stimulation (LFS) of Cg1 in particular would increase persistence in the WLT. Contrary to our predictions, LFS of Cg1 resulted in shorter session duration, lower break weights, and fewer attempts on the break weight. High-frequency stimulation of Cg1 led to an increase in time spent off-task. LFS of the anterior insula was associated with a marginal increase in attempts on the break weight. Taken together our data suggest that stimulation of the rodent Cg1 during an effortful task alters certain aspects of effortful behavior, while insula stimulation has little effect.
Promoter Hypermethylation Analysis of Host Genes in Cervical Cancer Patients With and Without Human Immunodeficiency Virus in Botswana
Authors: Tawe Leabaneng , Grover Surbhi , Zetola Nicola , Robertson Erle S. , Gaseitsiwe Simani , Moyo Sikhulile , Kasvosve Ishmael , Paganotti Giacomo M. , Narasimhamurthy Mohan
Published: February 2021

Background: Epidemics of human immunodeficiency virus (HIV) and cervical cancer are interconnected. DNA hypermethylation of host genes' promoter in cervical lesions has also been recognized as a contributor to cervical cancer progression.

Methods: For this purpose we analyzed promoter methylation of four tumor suppressor genes (RARB, CADM1, DAPK1 and PAX1) and explored their possible association with cervical cancer in Botswana among women of known HIV status. Overall, 228 cervical specimens (128 cervical cancers and 100 non-cancer subjects) were used. Yates-corrected chi-square test and Fisher's exact test were used to explore the association of promoter methylation for each host gene and cancer status. Subsequently, a logistic regression analysis was performed to find which factors, HIV status, high risk-HPV genotypes, patient's age and promoter methylation, were associated with the following dependent variables: cancer status, cervical cancer stage and promoter methylation rate.

Results: In patients with cervical cancer the rate of promoter methylation observed was greater than 64% in all the genes studied. Analysis also showed a higher risk of cervical cancer according to the increased number of methylated promoter genes (OR = 6.20; 95% CI: 3.66–10.51; P < 0.001). RARB methylation showed the strongest association with cervical cancer compared to other genes (OR = 15.25; 95% CI: 6.06–40.0; P < 0.001). Cervical cancer and promoter methylation of RARB and DAPK1 genes were associated with increasing age (OR = 1.12; 95% CI: 1.01-1.26; P = 0.037 and OR = 1.05; 95% CI: 1.00-1.10; P = 0.040). The presence of epigenetic changes at those genes appeared to be independent of HIV status among subjects with cervical cancer. Moreover, we found that cervical cancer stage was influenced by RARB (χ2= 7.32; P = 0.002) and CADM1 (χ2=12.68; P = 0.013) hypermethylation, and HIV status (χ2= 19.93; P = 0.001).

Conclusion: This study confirms the association between invasive cervical cancer and promoter gene methylation of tumor suppressing genes at the site of cancer. HIV infection did not show any association to methylation changes in this group of cervical cancer patients from Botswana. Further studies are needed to better understand the role of HIV in methylation of host genes among cancer subjects leading to cervical cancer progression.
Boron Neutron Capture Therapy: A Review of Clinical Applications
Authors: Malouff Timothy D. , Seneviratne Danushka S. , Ebner Daniel K. , Stross William C. , Waddle Mark R. , Trifiletti Daniel M. , Krishnan Sunil
Published: February 2021

Boron neutron capture therapy (BNCT) is an emerging treatment modality aimed at improving the therapeutic ratio for traditionally difficult to treat tumors. BNCT utilizes boronated agents to preferentially deliver boron-10 to tumors, which, after undergoing irradiation with neutrons, yields litihium-7 and an alpha particle. The alpha particle has a short range, therefore preferentially affecting tumor tissues while sparing more distal normal tissues. To date, BNCT has been studied clinically in a variety of disease sites, including glioblastoma multiforme, meningioma, head and neck cancers, lung cancers, breast cancers, hepatocellular carcinoma, sarcomas, cutaneous malignancies, extramammary Paget’s disease, recurrent cancers, pediatric cancers, and metastatic disease. We aim to provide an up-to-date and comprehensive review of the studies of each of these disease sites, as well as a review on the challenges facing adoption of BNCT.
The Clinical Characteristics and Prediction Nomograms for Primary Spine Malignancies
Authors: Zhou Lei , Huang Runzhi , Wei Ziheng , Meng Tong , Yin Huabin
Published: February 2021

Background

Primary spine malignancies (PSMs) are relatively rare in bone tumors. Due to their rarity, the clinical characteristics and prognostic factors are still ambiguous. In this study, we aim to identify the clinical features and proposed prediction nomograms for patients with PSMs.

Methods

Patients diagnosed with PSMs including chordoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, and malignant giant cell tumor of bone (GCTB) between 1975 and 2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. The patient and tumor characteristics were described based on clinical information. The significant prognostic factors of overall survival (OS) and cancer-specific survival (CSS) were identified by the univariate and multivariate Cox analysis. Then, the nomograms for OS and CSS were established based on the selected predictors and their accuracy was explored by the Cox–Snell residual plot, area under the curve (AUC) of receiver operator characteristic (ROC) and calibration curve.

Results

The clinical information of 1,096 patients with PSMs was selected from the SEER database between 1975 and 2016. A total of 395 patients were identified with full survival and treatment data between 2004 and 2016. Chordoma is the commonest tumor with 400 cases, along 172 cases with osteosarcoma, 240 cases with chondrosarcoma, 262 cases with Ewing sarcoma and 22 cases with malignant GCTB. The univariate and multivariate analyses revealed that older age (Age > 60), distant metastasis, chemotherapy, and Surgery were independent predictors for OS and/or CSS. Based on these results, the nomograms were established with a better applicability (AUC for CSS: 0.784; AUC for OS: 0.780).

Conclusions

This study provides the statistics evidence for the clinical characteristics and predictors for patients with PSMs based on a large size population. Additionally, precise prediction nomograms were also established with a well-applicability.
The Functional Reorganization of Language Network Modules in Glioma Patients: New Insights From Resting State fMRI Study
Authors: Jin Lu , Li Chuzhong , Zhang Yazhuo , Yuan Taoyang , Ying Jianyou , Zuo Zhentao , Gui Songbai
Published: February 2021

Background

Prior investigations of language functions have focused on the response profiles of particular brain regions. However, the specialized and static view of language processing does not explain numerous observations of functional recovery following brain surgery. To investigate the dynamic alterations of functional connectivity (FC) within language network (LN) in glioma patients, we explored a new flexible model based on the neuroscientific hypothesis of core-periphery organization in LN.

Methods

Group-level LN mapping was determined from 109 glioma patients and forty-two healthy controls (HCs) using independent component analysis (ICA). FC and mean network connectivity (mNC: l/rFCw, FCb, and FCg) were compared between patients and HCs. Correlations between mNC and tumor volume (TV) were calculated.

Results

We identified ten separate LN modules from ICA. Compared to HCs, glioma patients showed a significant reduction in language network functional connectivity (LNFC), with a distinct pattern modulated by tumor position. Left hemisphere gliomas had a broader impact on FC than right hemisphere gliomas, with more reduced edges away from tumor sites (p=0.011). mNC analysis revealed a significant reduction in all indicators of FC except for lFCw in right hemisphere gliomas. These alterations were associated with TV in a double correlative relationship depending on the tumor position across hemispheres.

Conclusion

Our findings emphasize the importance of considering the modulatory effects of core-periphery mechanisms from a network perspective. Preoperative evaluation of changes in LN caused by gliomas could provide the surgeon a reference to optimize resection while maintaining functional balance.
Oxygen Deprivation Modulates EGFR and PD-L1 in Squamous Cell Carcinomas of the Head and Neck
Authors: Zahnreich Sebastian , Gebrekidan Senayit , Multhoff Gabriele , Vaupel Peter , Schmidberger Heinz , Mayer Arnulf
Published: February 2021

Abundance and signaling of the epidermal growth factor receptor (EGFR) and programmed cell death protein ligand 1 (PD-L1) in head and neck squamous cell carcinoma (HNSCC) are not only genetically determined but are also subject to the traits of the tumor microenvironment, which has hitherto not been clarified completely. We investigated the impact of hypoxia on the EGFR system and on PD-L1 in six HPV negative HNSCC cell lines in vitro and in FaDu xenografts in vivo. Protein levels of EGFR, AKT, pAKT, ERK1/2, pERK1/2, CA IX, cleaved PARP (apoptosis), LC3B (autophagy), and PD-L1 were quantified by western blot after oxygen deprivation or CoCl2, staurosporine, and erlotinib treatment. In FaDu xenograft tumors the expression of EGFR, CA IX andCD34 staining were analyzed. Reduced oxygen supply strongly downregulated EGFR protein levels and signaling in FaDu cells in vitro and in vivo, and a transient downregulation of EGFR signaling was found in three other HNSCC cell lines. PD-L1 was affected by oxygen deprivation in only one HNSCC cell line showing increased protein amounts. The results of this study indicate a significant impact of the traits of the tumor microenvironment on crucial molecular targets of cancer therapies with high clinical relevance for therapy resistance and response in HNSCC.
CT-Based Radiomics Signatures for Predicting the Risk Categorization of Thymic Epithelial Tumors
Authors: Liu Jin , Yin Ping , Wang Sicong , Liu Tao , Sun Chao , Hong Nan
Published: February 2021

Objectives

This study aims to assess the performance of radiomics approaches based on 3D computed tomography (CT), clinical and semantic features in predicting the pathological classification of thymic epithelial tumors (TETs).

Methods

A total of 190 patients who underwent surgical resection and had pathologically confirmed TETs were enrolled in this retrospective study. All patients underwent non-contrast-enhanced CT (NECT) scans and contrast-enhanced CT (CECT) scans before treatment. A total of 396 hand-crafted radiomics features of each patient were extracted from the volume of interest in NECT and CECT images. We compared three clinical features and six semantic features (observed radiological traits) between patients with TETs. Two triple-classification radiomics models (RMs), two corresponding clinical RMs, and two corresponding clinical-semantic RMs were built to identify the types of the TETs. The area under the receiver operating characteristic curve (AUC) and accuracy (ACC) were useful to evaluate the different models.

Results

Of the 190 patients, 83 had low-risk thymoma, 58 had high-risk thymoma, and 49 had thymic carcinoma. Clinical features (Age) and semantic features (mediastinal fat infiltration, mediastinal lymph node enlargement, and pleural effusion) were significantly different among the groups(P < 0.001). In the validation set, the NECT-based clinical RM (AUC = 0.770 for low-risk thymoma, 0.689 for high-risk thymoma, and 0.783 for thymic carcinoma; ACC = 0.569) performed better than the CECT-based clinical-semantic RM (AUC = 0.785 for low-risk thymoma, 0.576 for high-risk thymoma, and 0.774 for thymic carcinoma; ACC = 0.483).

Conclusions

NECT-based and CECT-based RMs may provide a non-invasive method to distinguish low-risk thymoma, high-risk thymoma, and thymic carcinoma, and NECT-based RMs performed better.

Advances in Knowledge

Radiomics models may be used for the preoperative prediction of the pathological classification of TETs.
A Risk Prediction Model by LASSO for Radiation-Induced Xerostomia in Patients With Nasopharyngeal Carcinoma Treated With Comprehensive Salivary Gland–Sparing Helical Tomotherapy Technique
Authors: Teng Feng , Fan Wenjun , Luo Yanrong , Xu Shouping , Gong Hanshun , Ge Ruigang , Zhang Xinxin , Wang Xiaoning , Ma Lin
Published: February 2021

Objective

This study aimed to develop a least absolute shrinkage and selection operator (LASSO)-based multivariable normal tissue complication probability (NTCP) model to predict radiation-induced xerostomia in patients with nasopharyngeal carcinoma (NPC) treated with comprehensive salivary gland–sparing helical tomotherapy technique.

Methods and Materials

LASSO with the extended bootstrapping technique was used to build multivariable NTCP models to predict factors of patient-reported xerostomia relieved by 50% and 80% compared with the level at the end of radiation therapy within 1 year and 2 years, R50-1year and R80-2years, in 203 patients with NPC. The model assessment was based on 10-fold cross-validation and the area under the receiver operating characteristic curve (AUC).

Results

The prediction model by LASSO with 10-fold cross-validation showed that radiation-induced xerostomia recovery could be predicted by prognostic factors of R50-1year (age, gender, T stage, UICC/AJCC stage, parotid Dmean, oral cavity Dmean, and treatment options) and R80-2years (age, gender, T stage, UICC/AJCC stage, oral cavity Dmean, N stage, and treatment options). These prediction models also demonstrated a good performance by the AUC.

Conclusion

The prediction models of R50-1year and R80-2years by LASSO with 10-fold cross-validation were recommended to validate the NTCP model before comprehensive salivary gland–sparing radiation therapy in patients with NPC.
Haploidentical Stem Cell Transplantation With a Novel Conditioning Regimen in Older Patients: A Prospective Single-Arm Phase 2 Study
Authors: Sun Yu-Qian , Han Ting-Ting , Wang Yu , Yan Chen-Hua , Wang Feng-Rong , Wang Zhi-Dong , Kong Jun , Chen Yu-Hong , Chen Huan , Han Wei , Chen Yao , Zhang Yuan-Yuan , Zhang Xiao-Hui , Xu Lan-Ping , Liu Kai-Yan , Huang Xiao-Jun
Published: February 2021

Objective: Haploidentical stem cell transplantation (haplo-SCT) has demonstrated encouraging results in younger patients. There is also an increasing need for haplo-SCT in older patients. However, the high risk of treatment-related mortality (TRM) in older patients is still a major concern. We aimed to investigate a novel conditioning regimen (Bu/Flu/Cy/ATG) followed by haplo-SCT in older patients.

Method: This prospective, single-arm clinical trial was performed at Peking University Institute of Hematology, China. Patients were enrolled if they were (1) diagnosed with acute leukemia or MDS; (2) without MSD and MUD, and with HID available; and (3) age ≥55 years. The Bu/Flu/Cy/ATG regimen consisted of the following agents: Ara-C (2 g/m2/day, injected i.v.) on days-10 and−9; BU (9.6 mg/kg, injected i.v. in 12 doses) on days-8,−7, and−6; Flu (30 mg/m2/day, injected i.v.) from day−6 to day−2; Cy (1 g/m2/day, injected i.v.) on days−5 and−4; semustine (250 mg/m2, orally) on day-3 and antithymocyte globulin (ATG) [2.5 mg/kg/day, rabbit, SangStat (Lyon, France)] on days−5,−4,−3, and−2. The primary endpoint was 1-year TRM.

Results: From April 1, 2018 to April 10, 2020, a total of 50 patients were enrolled. All patients achieved neutrophil engraftment with complete donor chimerism. The cumulative incidence of grade 2-4 aGVHD at day-100 was 22.0%. The cumulative incidences of CMV viremia and EBV viremia on day 100 were 68.0 and 20.0%, respectively. The cumulative incidence of TRM at 1-year was 23.3%. and the cumulative incidence of relapse (CIR) at 1 year after transplantation was 16.5%. The overall survival (OS) and leukemia-free survival (LFS) at 1 year were 63.5 and 60.2%, respectively. The outcomes were also comparable with patients who received Bu/Cy/ATG regimen using a propensity score matching method.

Conclusions: In conclusion, this study suggested that a novel conditioning regimen followed by haploidentical HSCT might be a promising option for older patients. The study was registered as a clinical trial.

Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03412409.
Is Additional Systematic Biopsy Necessary in All Initial Prostate Biopsy Patients With Abnormal MRI?
Authors: Cheng Xueqing , Xu Jinshun , Chen Yuntian , Liu Zhenhua , Sun Guangxi , Yang Ling , Yao Jin , Zeng Hao , Song Bin
Published: February 2021

Purpose

To determine whether additional systematic biopsy is necessary in all biopsy naïve patients with MRI visible lesions by taking PI-RADS score and prostate volume into consideration.

Materials and Methods

Patients who underwent combined systematic biopsy (SB) and cognitive MRI-targeted biopsy (TB) in our hospital between May 2018 and June 2020 were retrospectively reviewed. The detection rate of clinical significant prostate cancer (csPCa), biopsy grade group (GG) concordance, and disease upgrading rate on radical prostatectomy were compared between SB and TB and further stratified by PI-RADS v2.0 category and prostate volume.

Results

A total of 234 patients were analyzed in this study. TB alone detected more csPCa and less clinically insignificant prostate cancer (cisPCa) than SB alone in the whole cohort (57.3 vs 53%, P = 0.041; 3.8 vs 7.7%, P = 0.049 respectively). The additional SB indicated only a marginal increase of csPCa detection but a remarkable increase of cisPCa detection compared with targeted biopsy (59.4 vs 57.3%, P = 0.064; 3.8 vs 7.7%, P = 0.012). As stratified by PI-RADS category, the difference of csPCa detection rate between TB and SB was not significant either in PI-RADS 5 subgroup (83.8 vs 76.3%, P = 0.07) or in PI-RADS 3–4 subgroup (43.5 vs 40.9%, P = 1.0). Additional SB decreased the rate of disease upgrading on radical prostatectomy (RP) than TB alone in PI-RADS 3–4 subgroup (14.5 vs 25.5%, P = 0.031) other than PI-RADS 5 subgroup (6 vs 6%, P = 1.0). When stratified by prostate volume (PV), TB alone detected more csPCa than SB in small prostate (PV < 30 ml) group (81.0 vs 71.0%, P = 0.021) but not in large prostate (PV ≥ 30 ml) group (44.0 vs 42.7%, P = 0.754). The additional SB did not significantly decrease the rate of disease upgrading on RP than TB alone in either small or large prostate (6.4 vs 8.5%, P = 1.0; 13.8 vs 22.4%, P = 0.063).

Conclusion

The combination biopsy method was no superior than targeted biopsy alone in PI-RADS 5 or in small volume prostate subgroup.
Case Report: Co-occurrence of Duchenne Muscular Dystrophy and Frontometaphyseal Dysplasia 1
Authors: Kim Jaewon , Lee Dong-Woo , Jang Ja-Hyun , Kim Myungshin , Yim Jisook , Jang Dae-Hyun
Published: February 2021

Herein, we present a rare case of co-occurring Duchenne muscular dystrophy (DMD) and frontometaphyseal dysplasia 1 (FMD1), two different X-linked diseases, in a 7-year-old boy. He presented with proximal muscle weakness and elevated creatine phosphokinase levels. A multiplex ligation-dependent probe amplification study ofDMDrevealed thede novoduplications of exons 2–37, thereby confirming the diagnosis of DMD. Initial evaluation revealed atypical features, such as facial dysmorphism, multiple joint contractures, and severe scoliosis, at an early age. However, these were overlooked and were assumed to be atypical manifestations of DMD. Then, the patient's maternal cousin was diagnosed with FMD1 with pathogenic missense variant inFLNA(NM_001110556.2: c.3557C>T/p.Ser1186Leu). A family genetic test revealed that the patient and his mother had the same pathogenic variant inFLNA. The patient's atypical manifestations were considered symptoms of FMD1. Therefore, if one disease does not fully explain the patient's clinical features, an expanded genetic study is needed to detect coincidental disease.
Advanced Approaches to Breast Cancer Classification and Diagnosis
Authors: Zubair M. , Wang S. , Ali N.
Published: February 2021

The International Agency for Research on Cancer (IARC) has recently reported a 66% increase in the global number of cancer deaths since 1960. In the US alone, about one in eight women is expected to develop invasive breast cancer(s) (breast cancer) at some point in their lifetime. Traditionally, a BC diagnosis includes mammography, ultrasound, and some high-end molecular bioimaging. Unfortunately, these techniques detect BC at a later stage. So early and advanced molecular diagnostic tools are still in demand. In the past decade, various histological and immuno-molecular studies have demonstrated that BC is highly heterogeneous in nature. Its growth pattern, cytological features, and expression of key biomarkers in BC cells including hormonal receptor markers can be utilized to develop advanced diagnostic and therapeutic tools. A cancer cell's progression to malignancy exhibits various vital biomarkers, many of which are still underrepresented in BC diagnosis and treatment. Advances in genetics have also enabled the development of multigene assays to detect genetic heterogeneity in BC. However, thus far, the FDA has approved only four such biomarkers—cancer antigens (CA); CA 15-3, CA 27-29, Human epidermal growth factor receptor 2 (HER2), and circulating tumor cells (CTC) in assessing BC in body fluids. An adequately structured portable-biosensor with its non-invasive and inexpensive point-of-care analysis can quickly detect such biomarkers without significantly compromising its specificity and selectivity. Such advanced techniques are likely to discriminate between BC and a healthy patient by accurately measuring the cell shape, structure, depth, intracellular and extracellular environment, and lipid membrane compositions. Presently, BC treatments include surgery and systemic chemo- and targeted radiation therapy. A biopsied sample is then subjected to various multigene assays to predict the heterogeneity and recurrence score, thus guiding a specific treatment by providing complete information on the BC subtype involved. Thus far, we have seven prognostic multigene signature tests for BC providing a risk profile that can avoid unnecessary treatments in low-risk patients. Many comparative studies on multigene analysis projected the importance of integrating clinicopathological information with genomic-imprint analysis. Current cohort studies such as MINDACT, TAILORx, Trans-aTTOM, and many more, are likely to provide positive impact on long-term patient outcome. This review offers consolidated information on currently available BC diagnosis and treatment options. It further describes advanced biomarkers for the development of state-of-the-art early screening and diagnostic technologies.
Thermodynamic Properties of the Parabolic-Well Fluid
Authors: López de Haro Mariano , Rodríguez‐Rivas Álvaro
Published: February 2021

The thermodynamic properties of the parabolic-well fluid are considered. The intermolecular interaction potential of this model, which belongs to the class of the so-called van Hove potentials, shares with the square-well and the triangular well potentials the inclusion of a hard-core and an attractive well of relatively short range. The analytic second virial coefficient for this fluid is computed explicitly and an equation of state is derived with the aid of the second-order thermodynamic perturbation theory in the macroscopic compressibility approximation and taking the hard-sphere fluid as the reference system. For this latter, the fully analytical expression of the radial distribution function, consistent with the Carnahan-Starling equation of state as derived within the rational function approximation method, is employed. The results for the reduced pressure of the parabolic-well fluid as a function of the packing fraction and two values of the range of the parabolic-well potential at different temperatures are compared with Monte Carlo and Event‐driven molecular dynamics simulation data. Estimates of the values of the critical temperature are also provided.
Volume Load-Induced Right Ventricular Failure in Rats Is Not Associated With Myocardial Fibrosis
Authors: Hagdorn Quint A. J. , Kurakula Kondababu , Koop Anne-Marie C. , Bossers Guido P. L. , Mavrogiannis Emmanouil , van Leusden Tom , van der Feen Diederik E. , de Boer Rudolf A. , Goumans Marie-José T. H. , Berger Rolf M. F.
Published: February 2021

Background

Right ventricular (RV) function and failure are key determinants of morbidity and mortality in various cardiovascular diseases. Myocardial fibrosis is regarded as a contributing factor to heart failure, but its importance in RV failure has been challenged. This study aims to assess whether myocardial fibrosis drives the transition from compensated to decompensated volume load-induced RV dysfunction.

Methods

Wistar rats were subjected to aorto-caval shunt (ACS, n = 23) or sham (control, n = 15) surgery, and sacrificed after 1 month, 3 months, or 6 months. Echocardiography, RV pressure-volume analysis, assessment of gene expression and cardiac histology were performed.

Results

At 6 months, 6/8 ACS-rats (75%) showed clinical signs of RV failure (pleural effusion, ascites and/or liver edema), whereas at 1 month and 3 months, no signs of RV failure had developed yet. Cardiac output has increased two- to threefold and biventricular dilatation occurred, while LV ejection fraction gradually decreased. At 1 month and 3 months, RV end-systolic elastance (Ees) remained unaltered, but at 6 months, RV Ees had decreased substantially. In the RV, no oxidative stress, inflammation, pro-fibrotic signaling (TGFβ1 and pSMAD2/3), or fibrosis were present at any time point.

Conclusions

In the ACS rat model, long-term volume load was initially well tolerated at 1 month and 3 months, but induced overt clinical signs of end-stage RV failure at 6 months. However, no myocardial fibrosis or increased pro-fibrotic signaling had developed. These findings indicate that myocardial fibrosis is not involved in the transition from compensated to decompensated RV dysfunction in this model.