bluuebunny/crossref_metadata_2025 huggingface dataset:
Phosphate-Solubilizing Pseudomonas sp. Strain WS32 Rhizosphere Colonization-Induced Expression Changes in Wheat Roots
Authors: Ou Kangmiao , He Xiangyi , Cai Ke , Zhao Weirong , Jiang Xiaoxun , Ai Wenfeng , Ding Yue , Cao Yuanyuan
Published: June 2022

Rhizosphere colonization is a pre-requisite for the favorable application of plant growth-promoting rhizobacteria (PGPR). Exchange and mutual recognition of signaling molecules occur frequently between plants and microbes. Here, the luciferase luxAB gene was electrotransformed into the phosphate-solubilizing strain Pseudomonas sp. WS32, a type of plant growth-promoting rhizobacterium with specific affinity for wheat. A labeled WS32 strain (WS32-L) was applied to determine the temporal and spatial traits of colonization within the wheat rhizosphere using rhizoboxes experimentation under natural condition. The effects of colonization on wheat root development and seedling growth were evaluated, and RNA sequencing (RNA-seq) was performed to explore the transcriptional changes that occur in wheat roots under WS32 colonization. The results showed that WS32-L could survive in the wheat rhizosphere for long periods and could expand into new zones following wheat root extension. Significant increases in seedling fresh and dry weight, root fresh and dry weight, root surface area, number of root tips, and phosphorus accumulation in the wheat leaves occurred in response to WS32 rhizosphere colonization. RNA-seq analysis showed that a total of 1485 genes in wheat roots were differentially expressed between the inoculated conditions and the uninoculated conditions. Most of the transcriptional changes occurred for genes annotated to the following functional categories: “phosphorus and other nutrient transport,” “hormone metabolism and organic acid secretion,” “flavonoid signal recognition,” “membrane transport,” and “transcription factor regulation.” These results are therefore valuable to future studies focused on the molecular mechanisms underlying the growth-promoting activities of PGPR on their host plants.
An Altered Metabolism in Leukocytes Showing in vitro igG Memory From SARS-CoV-2-Infected Patients
Authors: Fanelli G. , Gevi F. , Zarletti G. , Tiberi M. , De Molfetta V. , Scapigliati G. , Timperio A. M.
Published: June 2022

Coronavirus disease 2019 (COVID 19) is a systemic infection that exerts a significant impact on cell metabolism. In this study we performed metabolomic profiling of 41 in vitro cultures of peripheral blood mononuclear cells (PBMC), 17 of which displayed IgG memory for spike-S1 antigen 60–90 days after infection. By using mass spectrometry analysis, a significant up-regulation of S-adenosyl-Homocysteine, Sarcosine and Arginine was found in leukocytes showing IgG memory. These metabolites are known to be involved in physiological recovery from viral infections and immune activities, and our findings might represent a novel and easy measure that could be of help in understanding SARS-Cov-2 effects on leukocytes.
Microglial Activation, Tau Pathology, and Neurodegeneration Biomarkers Predict Longitudinal Cognitive Decline in Alzheimer’s Disease Continuum
Authors: Chen Yi-He , Lin Rong-Rong , Huang Hui-Feng , Xue Yan-Yan , Tao Qing-Qing
Published: June 2022

Purpose

Biomarkers used for predicting longitudinal cognitive change in Alzheimer’s disease (AD) continuum are still elusive. Tau pathology, neuroinflammation, and neurodegeneration are the leading candidate predictors. We aimed to determine these three aspects of biomarkers in cerebrospinal fluid (CSF) and plasma to predict longitudinal cognition status using Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.

Patients and Methods

A total of 430 subjects including, 96 cognitive normal (CN) with amyloid β (Aβ)-negative, 54 CN with Aβ-positive, 195 mild cognitive impairment (MCI) with Aβ-positive, and 85 AD with amyloid-positive (Aβ-positive are identified by CSF Aβ42/Aβ40 < 0.138). Aβ burden was evaluated by CSF and plasma Aβ42/Aβ40 ratio; tau pathology was evaluated by CSF and plasma phosphorylated-tau (p-tau181); microglial activation was measured by CSF soluble TREM2 (sTREM2) and progranulin (PGRN); neurodegeneration was measured by CSF and plasma t-tau and structural magnetic resonance imaging (MRI); cognition was examined annually over the subsequent 8 years using the Alzheimer’s Disease Assessment Scale Cognition 13-item scale (ADAS13) and Mini-Mental State Exam (MMSE). Linear mixed-effects models (LME) were applied to assess the correlation between biomarkers and longitudinal cognition decline, as well as their effect size on the prediction of longitudinal cognitive decline.

Results

Baseline CSF Aβ42/Aβ40 ratio was decreased in MCI and AD compared to CN, while CSF p-tau181 and t-tau increased. Baseline CSF sTREM2 and PGRN did not show any differences in MCI and AD compared to CN. Baseline brain volumes (including the hippocampal, entorhinal, middle temporal lobe, and whole-brain) decreased in MCI and AD groups. For the longitudinal study, there were significant interaction effects of CSF p-tau181 × time, plasma p-tau181 × time, CSF sTREM2 × time, and brain volumes × time, indicating CSF, and plasma p-tau181, CSF sTREM2, and brain volumes could predict longitudinal cognition deterioration rate. CSF sTREM2, CSF, and plasma p-tau181 had similar medium prediction effects, while brain volumes showed stronger effects in predicting cognition decline.

Conclusion

Our study reported that baseline CSF sTREM2, CSF, and plasma p-tau181, as well as structural MRI, could predict longitudinal cognitive decline in subjects with positive AD pathology. Plasma p-tau181 can be used as a relatively noninvasive reliable biomarker for AD longitudinal cognition decline prediction.
Induction of Autophagy Promotes Clearance of RHOP23H Aggregates and Protects From Retinal Degeneration
Authors: Intartaglia Daniela , Giamundo Giuliana , Naso Federica , Nusco Edoardo , Di Giulio Simona , Salierno Francesco Giuseppe , Polishchuk Elena , Conte Ivan
Published: June 2022

Autophagy is a critical metabolic process that acts as a major self-digestion and recycling pathway contributing to maintain cellular homeostasis. An emerging field of research supports the therapeutic modulation of autophagy for treating human neurodegenerative disorders, in which toxic aggregates are accumulated in neurons. Our previous study identified Ezrin protein as an inhibitor of autophagy and lysosomal functions in the retina; thus, in turn, identifying it as a potential pharmacological target for increasing retinal cell clearance to treat inherited retinal dystrophies in which misfolded proteins have accumulated. This study aimed to verify the therapeutic inhibition of Ezrin to induce clearance of toxic aggregates in a mouse model for a dominant form of retinitis pigmentosa (i.e., RHOP23H/+). We found that daily inhibition of Ezrin significantly decreased the accumulation of misfolded RHOP23H aggregates. Remarkably, induction of autophagy, by a drug-mediated pulsatile inhibition of Ezrin, promoted the lysosomal clearance of disease-linked RHOP23H aggregates. This was accompanied with a reduction of endoplasmic reticulum (ER)-stress, robust decrease of photoreceptors' cell death, amelioration in both retinal morphology and function culminating in a better preservation of vision. Our study opens new perspectives for a pulsatile pharmacological induction of autophagy as a mutation-independent therapy paving the way toward a more effective therapeutic strategy to treat these devastating retinal disorders due to an accumulation of intracellular toxic aggregates.
Genome Sequencing Variations in the Octodon degus, an Unconventional Natural Model of Aging and Alzheimer's Disease
Authors: Hurley Michael J. , Urra Claudio , Garduno B. Maximiliano , Bruno Agostino , Kimbell Allison , Wilkinson Brent , Marino-Buslje Cristina , Ezquer Marcelo , Ezquer Fernando , Aburto Pedro F. , Poulin Elie , Vasquez Rodrigo A. , Deacon Robert , Avila Ariel , Altimiras Francisco , Whitney Vanderklish Peter , Zampieri Guido , Angione Claudio , Constantino Gabriele , Holmes Todd C. , Coba Marcelo P. , Xu Xiangmin , Cogram Patricia
Published: June 2022

The degu (Octodon degus) is a diurnal long-lived rodent that can spontaneously develop molecular and behavioral changes that mirror those seen in human aging. With age some degu, but not all individuals, develop cognitive decline and brain pathology like that observed in Alzheimer's disease including neuroinflammation, hyperphosphorylated tau and amyloid plaques, together with other co-morbidities associated with aging such as macular degeneration, cataracts, alterations in circadian rhythm, diabetes and atherosclerosis. Here we report the whole-genome sequencing and analysis of the degu genome, which revealed unique features and molecular adaptations consistent with aging and Alzheimer's disease. We identified single nucleotide polymorphisms in genes associated with Alzheimer's disease including a novel apolipoprotein E (Apoe) gene variant that correlated with an increase in amyloid plaques in brain and modified the in silico predicted degu APOE protein structure and functionality. The reported genome of an unconventional long-lived animal model of aging and Alzheimer's disease offers the opportunity for understanding molecular pathways involved in aging and should help advance biomedical research into treatments for Alzheimer's disease.
Mediation of the APOE Associations With Cognition Through Cerebral Blood Flow: The CIBL Study
Authors: Wang Yan-Li , Sun Mengfan , Wang Fang-Ze , Wang Xiaohong , Jia Ziyan , Zhang Yuan , Li Runzhi , Jiang Jiwei , Wang Linlin , Li Wenyi , Sun Yongan , Chen Jinglong , Zhang Cuicui , Shi Baolin , Liu Jianjian , Liu Xiangrong , Xu Jun
Published: June 2022

Background

The ε4 allele of the apolipoprotein E (APOE) gene is a strong genetic risk factor for aging-related cognitive decline. However, the causal connection between ε4 alleles and cognition is not well understood. The objective of this study was to identify the roles of cerebral blood flow (CBF) in cognitive-related brain areas in mediating the associations of APOE with cognition.

Methods

The multiple linear regression analyses were conducted on 369 subjects (mean age of 68.8 years; 62.9% of women; 29.3% of APOE ε4 allele carriers). Causal mediation analyses with 5,000 bootstrapped iterations were conducted to explore the mediation effects.

Result

APOE ε4 allele was negatively associated with cognition (P < 0.05) and CBF in the amygdala, hippocampus, middle temporal gyrus, posterior cingulate, and precuneus (all P < 0.05). The effect of the APOE genotype on cognition was partly mediated by the above CBF (all P < 0.05).

Conclusion

CBF partially mediates the potential links between APOE genotype and cognition. Overall, the APOE ε4 allele may lead to a dysregulation of the vascular structure and function with reduced cerebral perfusion, which in turn leads to cognitive impairment.
Brain Somatic Variant in Ras-Like Small GTPase RALA Causes Focal Cortical Dysplasia Type II
Authors: Xu Han , Gao Kai , Liu Qingzhu , Wang Tianshuang , Zhang Zhongbin , Cai Lixin , Wu Ye , Jiang Yuwu
Published: June 2022

Purpose

In our group’s previous study, we performed deep whole-exome sequencing and targeted amplicon sequencing in the postoperative brain tissue of epilepsy patients with focal cortical dysplasia type II (FCD II). We identified the first somatic variant of RALA in the brain tissue of a child with FCD type IIb. RALA encodes a small GTPase of the Ras superfamily. To date, the role of RALA in brain development is not yet known. In this study, we reported that the RALA somatic variant led to FCD type II through activation of the mammalian target of rapamycin (mTOR) pathways.

Materials and Methods

HEK293T cells were transfected in vitro to analyze the expression of the RalA protein, as well as phosphorylated S6 (P-S6), one of the major markers of mTOR pathway activation, RalA GTPase activity, and the interaction between RalA and its downstream binding effectors. In vivo, wild-type, and mutant RALA plasmids were transfected into the local cortex of mice using in utero electroporation to evaluate the effect of RALA c.G482A on neuronal migration.

Results

The RALA c.G482A mutation increased RalA protein expression, the abnormal activation of the mTOR pathways, RalA GTPase activity, and binding to downstream effectors. RALA c.G482A local transfection in the embryonic brain in utero induced abnormal cortical neuron migration in mice.

Conclusion

This study demonstrated for the first time that the somatic gain-of-function variant of RALA activates the mTOR pathway and leads to neuronal migration disorders in the brain, facilitating the development of FCD II. Therefore, RALA brain somatic mutation may be one of the pathogenic mechanisms leading to FCD II, which is always related to drug-resistant epilepsy in children. However, more somatic variations of this gene are required to be confirmed in more FCD II patient brain samples.
A Real-Time EMG-Based Fixed-Bandwidth Frequency-Domain Embedded System for Robotic Hand
Authors: Chen Biao , Chen Chaoyang , Hu Jie , Nguyen Thomas , Qi Jin , Yang Banghua , Chen Dawei , Alshahrani Yousef , Zhou Yang , Tsai Andrew , Frush Todd , Goitz Henry
Published: June 2022

The signals from electromyography (EMG) have been used for volitional control of robotic assistive devices with the challenges of performance improvement. Currently, the most common method of EMG signal processing for robot control is RMS (root mean square)-based algorithm, but system performance accuracy can be affected by noise or artifacts. This study hypothesized that the frequency bandwidths of noise and artifacts are beyond the main EMG signal frequency bandwidth, hence the fixed-bandwidth frequency-domain signal processing methods can filter off the noise and artifacts only by processing the main frequency bandwidth of EMG signals for robot control. The purpose of this study was to develop a cost-effective embedded system and short-time Fourier transform (STFT) method for an EMG-controlled robotic hand. Healthy volunteers were recruited in this study to identify the optimal myoelectric signal frequency bandwidth of muscle contractions. The STFT embedded system was developed using the STM32 microcontroller unit (MCU). The performance of the STFT embedded system was compared with RMS embedded system. The results showed that the optimal myoelectric signal frequency band responding to muscle contractions was between 60 and 80 Hz. The STFT embedded system was more stable than the RMS embedded system in detecting muscle contraction. Onsite calibration was required for RMS embedded system. The average accuracy of the STFT embedded system is 91.55%. This study presents a novel approach for developing a cost-effective and less complex embedded myoelectric signal processing system for robot control.
Exosomes Derived From Umbilical Cord Mesenchymal Stem Cells Treat Cutaneous Nerve Damage and Promote Wound Healing
Authors: Zhu Ziying , Zhang Xiaona , Hao Haojie , Xu Heran , Shu Jun , Hou Qian , Wang Min
Published: June 2022

Wound repair is a key step in the treatment of skin injury caused by burn, surgery, and trauma. Various stem cells have been proven to promote wound healing and skin regeneration as candidate seed cells. Therefore, exosomes derived from stem cells are emerging as a promising method for wound repair. However, the mechanism by which exosomes promote wound repair is still unclear. In this study, we reported that exosomes derived from umbilical cord mesenchymal stem cells (UC-MSCs) promote wound healing and skin regeneration by treating cutaneous nerve damage. The results revealed that UC-MSCs exosomes (UC-MSC-Exo) promote the growth and migration of dermal fibroblast cells. In in vitro culture, dermal fibroblasts could promote to nerve cells and secrete nerve growth factors when stimulated by exosomes. During the repair process UC-MSC-Exo accelerated the recruitment of fibroblasts at the site of trauma and significantly enhanced cutaneous nerve regeneration in vivo. Interestingly, it was found that UC-MSC-Exo could promote wound healing and skin regeneration by recruiting fibroblasts, stimulating them to secrete nerve growth factors (NGFs) and promoting skin nerve regeneration. Therefore, we concluded that UC-MSC-Exo promote cutaneous nerve repair, which may play an important role in wound repair and skin regeneration.
OnabotulinumtoxinA Dosing, Disease Severity, and Treatment Benefit in Patients With Cervical Dystonia: A Cohort Analysis From CD PROBE
Authors: Agarwal Pinky , Barbano Richard , Moore Henry , Schwartz Marc , Zuzek Aleksej , Sadeghi Marjan , Patel Atul
Published: June 2022

Introduction

The Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE) study (ClinicalTrials.gov identifier: NCT00836017), a multicenter, prospective, observational registry, was designed to identify real-world practices and outcomes for patients with cervical dystonia (CD) treated with onabotulinumtoxinA (onabotA). This secondary analysis from CD PROBE aims to determine the impact of presentation subtype on onabotA utilization and CD severity.

Materials and Methods

The study cohort includes those who completed all 3 treatments, 4 office visits, and had data recorded for all assessments. Patient outcomes were assessed with the Cervical Dystonia Impact Profile (CDIP-58), Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), and determination of CD severity. Treatment interval, dose, and adverse events (AEs) were also recorded. Data were stratified according to prior exposure to botulinum toxins (BoNTs) and analyzed with descriptive statistics.

Results

Torticollis was the most common presentation subtype in the study cohort (N = 350); the proportion of patients with torticollis was highest in those with severe disease. At each treatment, between 40.7 and 65.2% of those categorized as severe shifted to moderate or mild severity after treatment. Sustained improvements in CDIP-58 and TWSTRS were observed regardless of prior exposure to BoNTs. Dosing of onabotA generally increased from injection 1 to injection 3 and tended to be lower for patients naïve to BoNT. Median time interval between injections for the study cohort was 94.0 to 97.5 days. The most common AEs (dysphagia, muscular weakness) and injection intervals were similar between naïve vs. non-naïve patients; there were no serious treatment-related AEs.

Conclusions

This secondary cohort analysis from CD PROBE demonstrates that three repeat treatments with onabotA at intervals consistent with labeling attenuated disease severity and neck pain, resulting in sustained improvements in physician- and patient-reported outcomes. No new safety signals were identified.
Comparison of First-Pass Effect in Aspiration vs. Stent-Retriever for Acute Intracranial ICA Occlusion
Authors: Hernández David , Serrano Elena , Molins Gemma , Zarco Federico , Chirife Oscar , Werner Mariano , Lara Blanca , Ramos Anna , Llull Laura , Requena Manuel , Cuevas Marta de Dios las , Remollo Sebastián , Piñana Carlos , López-Rueda Antonio
Published: June 2022

The purpose of this study is to evaluate the best endovascular approach (aspiration or stent-retriever) and the impact of stent retriever size and length on clinical and angiographic outcomes in patients with acute intracranial ICA occlusion. We conducted a retrospective analysis of a prospective database of consecutive patients with acute intracranial ICA occlusion undergoing endovascular treatment in four Comprehensive Stroke Center between June-2019 and December-2020. We include 121 patients; Stent-retriever (SR) was used as first technical approach in 107 patients (88.4%) and aspiration was used in 14 patients (11.6%). SR group had higher rate of FPE compared to aspiration group (29 vs. 0%, p = 0.02). In SR subgroup, treatment highlighted higher FPE in the 6 × 50 SR (37.7%), than in the rest of the SR which are 21.2% (4–5 mm size and 20–50 mm length SR) and 19% (6 mm size and 25–40 mm length SR), but it was not found to be statistically significant. There were no other significant differences across the groups regarding primary angiographic or clinical outcomes. In our intracranial ICA occlusion series, stent retrievers were superior to direct aspiration in obtaining FPEs and mFPEs, and longer devices achieved better results with no statistically significant difference. Further studies evaluating the effects of different ICA clot removal approaches are warranted to confirm these results.
Event-Related Potential Assessment of Visual Perception Abnormality in Patients With Obstructive Sleep Apnea: A Preliminary Study
Authors: Yang Chao , Wang Changming , Chen Xuanyu , Xiao Bing , Fu Na , Ren Bo , Liu Yi
Published: June 2022

This study investigated the effect of obstructive sleep apnea (OSA) on the neural mechanism of visual perception. A preliminary case-control study was conducted. Seventeen patients with moderate to severe OSA in the sleep center of Civil Aviation General Hospital and 20 healthy controls matched for age, sex, and education were recruited. The participants accepted the perceptual contour integration task, compared the differences in behavioral indicators between the two groups, and compared the differences in electroencephalography (EEG) data between the two groups through event-related potential (ERP) technology. The groups did not differ significantly in age and gender, but they differed significantly in body mass index (BMI) (OSA higher than healthy controls, p < 0.05). The groups were not statistically different in terms of sleep structure and total sleep time. AHI, sleep efficiency, and minimal SaO2 value in the OSA group were significantly different from those of the control group. The results showed that the average reaction time of the OSA group was significantly longer than that of the healthy control group in the contour integration task. There was no significant difference in the accuracy rate. The results of EEG showed that the amplitudes of N100 of the OSA group were significantly higher than those of the control group at O1, Oz, and O2 electrodes. There was no significant difference in latency between the two groups. At the FCz electrode, the amplitudes of N200 of the OSA group were significantly higher than those of the control group. Therefore, we concluded that in the early stage of the perceptual integration task, although the neural response activity of patients with moderate and severe OSA was not accelerated, they need to call on more psychological resources, activate more neurons in the contour global recognition processing stage, and the compensatory effect of frontal lobe appeared in the stage of visual perception.
Congenital Infection Influence on Early Brain Development Through the Gut-Brain Axis
Authors: Kirschen Gregory W. , Panda Snigdha , Burd Irina
Published: June 2022

The mechanisms by which various pathogens cause congenital infections have been studied extensively, aiding in the understanding of the detrimental effects these infections can have on fetal/neonatal neurological development. Recent studies have focused on the gut-brain axis as pivotal in neurodevelopment, with congenital infections causing substantial disruptions. There remains controversy surrounding the purported sterility of the placenta as well as concerns regarding the effects of exposure to antibiotics used during pregnancy on neonatal microbiome development and how early exposure to microbes or antibiotics can shape the gut-brain axis. Long-term neurodevelopmental consequences, such as autism spectrum disorder, attention deficit hyperactivity disorder, and cerebral palsy, may be attributable, in part, to early life infection and changes in the immature gut microbiome. The goal of this review is thus to critically evaluate the current evidence related to early life infection affecting neurodevelopment through the gut-brain axis.
Malignant Myoepithelioma of the Head and Neck: Demographics, Clinicopathological Characteristics, Treatment, and Prognosis
Authors: Wang Jia-Qi , Deng Rong-Xin , Liu Hui , Luo Yuan , Lu Meng-Meng , Yang Zhi-Cheng
Published: June 2022

Malignant myoepithelioma of the head and neck (HNMM) is a rare malignancy, and its characteristics and survival rates have not been well-defined. This study aimed to define the epidemiology of HNMM and identify the prognostic factors associated with the disease. Data on all patients diagnosed with HNMM between 1991 and 2016 were gathered from the Surveillance Epidemiology and End Results (SEER) database. The demographics, clinicopathological characteristics, treatment, and prognoses of the patients were described. Cox regression analysis was used to identify the prognostic factors, and the prognostic nomograms for overall survival (OS) and disease-specific survival (DSS) were constructed. A total of 333 cases of HNMM were identified. The average age at diagnosis was 60.6 years, and 50.1% of the patients were men. After diagnosis, 46.2% of patients underwent surgery alone, 43.5% of patients underwent surgery and radiotherapy, and 3.6% of patients received only radiotherapy. Survival analysis showed that the 5-year OS and DSS for all HNMM patients were 69.7 and 82.1%, respectively. In the multivariate analysis model, the undifferentiated pathological grade (P <0.05) and M1 in the M category (P <0.01) were independent prognostic factors for poor OS and DSS, whereas the use of surgical resection was an independent favorable prognostic factor for both OS and DSS (P <0.05). The prognostic nomograms for OS and DSS prediction were constructed; the C-index values for OS and DSS prediction were 0.78 (95% CI 0.70–0.86) and 0.79 (95% CI 0.67–0.90), respectively. In conclusion, this SEER data-based study demonstrated that HNMM patients often had a favorable prognosis, and distant metastasis, pathological grade, and the use of surgery contributed to their survival. Furthermore, we developed a prognostic nomogram to predict OS and DSS for HNMM patients to aid physicians in the clinical management of this rare disease.
Retrospective Clinical Evaluation of a Decision-Support Software for Adaptive Radiotherapy of Head and Neck Cancer Patients
Authors: Gros Sebastien A. A. , Santhanam Anand P. , Block Alec M. , Emami Bahman , Lee Brian H. , Joyce Cara
Published: June 2022

Purpose

This study aimed to evaluate the clinical need for an automated decision-support software platform for adaptive radiation therapy (ART) of head and neck cancer (HNC) patients.

Methods

We tested RTapp (SegAna), a new ART software platform for deciding when a treatment replan is needed, to investigate a set of 27 HNC patients’ data retrospectively. For each fraction, the software estimated key components of ART such as daily dose distribution and cumulative doses received by targets and organs at risk (OARs) from daily 3D imaging in real-time. RTapp also included a prediction algorithm that analyzed dosimetric parameter (DP) trends against user-specified thresholds to proactively trigger adaptive re-planning up to four fractions ahead. The DPs evaluated for ART were based on treatment planning dose constraints. Warning (V95<95%) and adaptation (V95<93%) thresholds were set for PTVs, while OAR adaptation dosimetric endpoints of +10% (DE10) were set for all Dmax and Dmean DPs. Any threshold violation at end of treatment (EOT) triggered a review of the DP trends to determine the threshold-crossing fraction Fx when the violations occurred. The prediction model accuracy was determined as the difference between calculated and predicted DP values with 95% confidence intervals (CI95).

Results

RTapp was able to address the needs of treatment adaptation. Specifically, we identified 18/27 studies (67%) for violating PTV coverage or parotid Dmean at EOT. Twelve PTVs had V95<95% (mean coverage decrease of −6.8 ± 2.9%) including six flagged for adaptation at median Fx= 6 (range, 1–16). Seventeen parotids were flagged for exceeding Dmean dose constraints with a median increase of +2.60 Gy (range, 0.99–6.31 Gy) at EOT, including nine with DP>DE10. The differences between predicted and calculated PTV V95 and parotid Dmean was up to 7.6% (mean ± CI95, −2.7 ± 4.1%) and 5 Gy (mean ± CI95, 0.3 ± 1.6 Gy), respectively. The most accurate predictions were obtained closest to the threshold-crossing fraction. For parotids, the results showed that Fx ranged between fractions 1 and 23, with a lack of specific trend demonstrating that the need for treatment adaptation may be verified for every fraction.

Conclusion

Integrated in an ART clinical workflow, RTapp aids in predicting whether specific treatment would require adaptation up to four fractions ahead of time.
Differentiation of Thyroid Nodules (C-TIRADS 4) by Combining Contrast-Enhanced Ultrasound Diagnosis Model With Chinese Thyroid Imaging Reporting and Data System
Authors: Zhu Tiantong , Chen Jiahui , Zhou Zimo , Ma Xiaofen , Huang Ying
Published: June 2022

Objectives

To establish a contrast-enhanced ultrasound (CEUS) diagnostic schedule by CEUS analysis of thyroid nodules of C-TIRADS 4. To establish a CEUS-TIRADS diagnostic model to differentiate thyroid nodules (C-TIRADS 4) by combining CEUS with Chinese thyroid imaging reporting and data system (C-TIRADS).

Methods

A total of 228 thyroid nodules (C-TIRADS 4) were estimated by CEUS. The arrival time, enhancement degree, enhancement homogeneity, enhancement pattern, enhancement ring, and wash-out time were analyzed in CEUS for all of the nodules. Multivariate factors logistic analysis was performed and a CEUS diagnostic schedule was established. If the nodule had a regular hyper-enhancement ring or got a score of less than 2 in CEUS analysis, CEUS-TIRADS subtracted 1 category. If the nodule got a score of 2 in the CEUS schedule, the CEUS-TIRADS category remained the same as before. If the nodule got a score of more than 2 in the CEUS schedule, CEUS-TIRADS added 1 category. When it reflected an absent enhancement in CEUS, the nodule was judged as CEUS-TIRADS 3. All of the C-TIRADS 4 nodules were re-graded by CEUS-TIRADS. We then compare the diagnosis performance of C-TIRADS, CEUS, and CEUS-TIRADS by sensitivity, specificity, and accuracy.

Results

Among the 228 C-TIRADS 4 nodules, 69 were determined as C-TIRADS 4a, 114 were C-TIRADS 4b, and 45 were C-TIRADS 4c. The sensitivity, specificity, and accuracy of C-TIRADS were 93.1%, 55.3%, and 74.6% respectively. The area under the curve was 0.753. Later arrival time, hypo-enhancement, heterogeneous enhancement, centripetal enhancement, and rapid washout were risk factors of malignancy in multivariate analysis. The sensitivity, specificity, and accuracy of CEUS were 78.7%, 87.5%, and 83.3% respectively. The area under the curve was 0.803. By CEUS-TIRADS diagnostic model combining CEUS with C-TIRADS, a total of 127 cases were determined as malignancy (111 were malignant and 16 were benign) and 101 were diagnosed as benign ones (5 were malignant and 96 were benign). The sensitivity, specificity, and accuracy of CEUS-TIRADS were 95.7%, 85.7%, and 92.1% respectively. The area under the curve was 0.916. The diagnostic performance of CEUS-TIRADS was significantly better than CEUS and C-TIRADS. The difference was statistically significant (P<0.05).

Conclusions

The diagnostic schedule of CEUS could get better diagnostic performance than US in the differentiation of thyroid nodules. The CEUS-TIRADS combining CEUS analysis with C-TIRADS could make up for the deficient sensibility of C-TIRADS, showing a better diagnostic performance than US and CEUS.
Prognostic Significance of FDG PET/CT in Esophageal Squamous Cell Carcinoma in the Era of the 8th AJCC/UICC Staging System
Authors: Lee Hyunjong , Lee Kyung Soo , Min Yang Won , Kim Hong Kwan , Zo Jae Ill , Shim Young Mog , Choi Joon Young
Published: June 2022

Introduction

Recently, the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system was updated for its 8th edition. F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is a useful imaging tool to diagnose and predict prognoses for esophageal cancer. However, there was no previous study to explore the role of FDG PET/CT in the staging system based on the 8th edition. The prognostic value of FDG PET/CT was investigated in patients with esophageal squamous cell carcinoma (SqCC) considering the new 8th AJCC/UICC staging system.

Methods

Subjects were 721 patients with esophageal SqCC undergoing pretherapeutic FDG PET/CT. Clinico-pathological variables and the maximum standardized uptake value (SUVmax) of the primary tumor were included in survival analysis. Subgroup analysis was performed to compare hazard ratios according to pathological stage and SUVmax. A new staging classification including FDG uptake was proposed.

Results

In multivariate survival analysis, pathological stage and SUVmax of the primary tumor were selected as independent prognostic factors for overall survival in both the 7th and 8th editions. The proposed new staging system showed better discrimination for overall survival between stage I and II than did the conventional staging system (hazard ratios: 2.250 vs. 1.341).

Conclusions

The FDG uptake of the primary tumor was found to be an independent prognostic factor along with pathological stage based on both 7th and 8th AJCC/UICC staging systems in patients with esophageal SqCC. The suggested new staging system including SUVmax was better for predicting prognoses than the conventional staging system.
Integrative Proteo-Genomic Analysis for Recurrent Survival Prognosis in Colon Adenocarcinoma
Authors: Ai FeiYan , Wang Wenhao , Liu Shaojun , Zhang Decai , Yang Zhenyu , Liu Fen
Published: June 2022

Background

The survival prognosis is the hallmark of cancer progression. Here, we aimed to develop a recurrence-related gene signature to predict the prognosis of colon adenocarcinoma (COAD).

Methods

The proteomic data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and genomic data from the cancer genomic maps [The Cancer Genome Atlas (TCGA)] dataset were analyzed to identify co-differentially expressed genes (cDEGs) between recurrence samples and non-recurrence samples in COAD using limma package. Functional enrichment analysis, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway was conducted. Univariate and multivariate Cox regressions were applied to identify the independent prognostic feature cDEGs and establish the signature whose performance was evaluated by Kaplan–Meier curve, receiver operating characteristic (ROC), Harrell’s concordance index (C-index), and calibration curve. The area under the receiver operating characteristic (ROC) curve (AUROC) and a nomogram were calculated to assess the predictive accuracy. GSE17538 and GSE39582 were used for external validation. Quantitative real-time PCR and Western blot analysis were carried out to validate our findings.

Results

We identified 86 cDEGs in recurrence samples compared with non-recurrence samples. These genes were primarily enriched in the regulation of carbon metabolic process, fructose and mannose metabolism, and extracellular exosome. Then, an eight-gene-based signature (CA12, HBB, NCF1, KBTBD11, MMAA, DMBT1, AHNAK2, and FBLN2) was developed to separate patients into high- and low-risk groups. Patients in the low-risk group had significantly better prognosis than those in the high-risk group. Four prognostic clinical features, including pathological M, N, T, and RS model status, were screened for building the nomogram survival model. The PCR and Western blot analysis results suggested that CA12 and AHNAK2 were significantly upregulated, while MMAA and DMBT1 were downregulated in the tumor sample compared with adjacent tissues, and in non-recurrent samples compared with non-recurrent samples in COAD.

Conclusion

These identified recurrence-related gene signatures might provide an effective prognostic predictor and promising therapeutic targets for COAD patients.
Low-Grade Uterine Endometrial Stromal Sarcoma: Prognostic Analysis of Clinico-Pathological Characteristics, Surgical Management, and Adjuvant Treatments. Experience From Two Referral Centers
Authors: Borella Fulvio , Bertero Luca , Cassoni Paola , Piovano Elisa , Gallio Niccolò , Preti Mario , Cosma Stefano , Ferraioli Domenico , Pace Luca , Mariani Luca , Biglia Nicoletta , Benedetto Chiara
Published: June 2022

Objective

Low-grade uterine endometrial stromal sarcoma (LG-ESS) is a rare tumor characterized by an overall good survival but showing a indolent behavior and a variable risk of recurrence. There is no clear consensus on the optimal management of these tumors and no prognostic or predictive factors have been established. With this study, we evaluated the prognostic relevance of several clinical, surgical, and pathological features in patients affected by LG-ESS to identify risk factors associated with recurrence.

Methods

We retrospectively analyzed 52 LG-ESS cases, treated from January 1st, 1994, to May 31st, 2020, in two referral centers. The relationship between recurrence and clinicopathological characteristics as well as surgical treatment was investigated. Risk of recurrence and disease-free survival (DFS) were estimated by Cox regression and the Kaplan-Meier analysis, respectively.

Results

Of 52 patients with LG-ESS, 8 experienced recurrence (15%). The median follow-up was 100 months (SD ± 96, range: 15–336). By univariate analysis, fragmentation/morcellation, tumor size, FIGO stage, higher mitotic count, presence of necrosis, and lymphovascular space invasion (LSVI) resulted associated with a poorer outcome. Conversely, the surgical modality (laparotomic vs laparoscopic and hysterectomy with bilateral salpingo-oophorectomy vs local excision) and pelvic lymphadenectomy were not. Even the different modalities of adjuvant therapy (hormonal therapy, radiotherapy, and chemotherapy) showed no prognostic significance. Tumor fragmentation/morcellation and higher mitotic count resulted independent prognostic variables at multivariate analysis.

Conclusions

This data supports the avoidance of any type of morcellation if LG-ESS is suspected preoperatively. Higher mitotic count and, possibly, tumor size, advanced FIGO stage, necrosis, and LVSI could be exploited to tailor the adjuvant therapy, but these results need to be confirmed in larger prospective studies.
Evaluation of Biological Effective Dose in Gamma Knife Staged Stereotactic Radiosurgery for Large Brain Metastases
Authors: Cui Taoran , Weiner Joseph , Danish Shabbar , Chundury Anupama , Ohri Nisha , Yue Ning , Wang Xiao , Nie Ke
Published: June 2022

Objective

Gamma knife (GK) staged stereotactic radiosurgery (Staged-SRS) has become an effective treatment option for large brain metastases (BMs); however, it has been challenging to evaluate the total dose because of tumor shrinkage between two staged sessions. This study aims to evaluate total biological effective dose (BED) in Staged-SRS, and to compare the BED with those in single-fraction SRS (SF-SRS) and hypo-fractionated SRS (HF-SRS).

Methods

Patients treated with GK Staged-SRS at a single institution were retrospectively included. The dose delivered in two sessions of Staged-SRS was summed using the deformable image registration. Each patient was replanned for SF-SRS and HF-SRS. The total BEDs were computed using the linear-quadratic model. Tumor BED98% and brain V84Gy2, equivalent to V12Gy in SF-SRS, were compared between SF-SRS, HF-SRS, and Staged-SRS plans with the Wilcoxon test.

Results

Twelve patients with 24 BMs treated with GK Staged-SRS were identified. We observed significant differences (p < 0.05) in tumor BED98% but comparable brain V84Gy2 (p = 0.677) between the Staged-SRS and SF-SRS plans. No dosimetric advantages of Staged-SRS over HF-SRS were observed. Tumor BED98% in the HF-SRS plans were significantly higher than those in the Staged-SRS plans (p < 0.05). Despite the larger PTVs, brain V84Gy2 in the HF-SRS plans remained lower (p < 0.05).

Conclusion

We presented an approach to calculate the composite BEDs delivered to both tumor and normal brain tissue in Staged-SRS. Compared to SF-SRS, Staged-SRS delivers a higher dose to tumor but maintains a comparable dose to normal brain tissue. Our results did not show any dosimetric advantages of Staged-SRS over HF-SRS.
Proliferation Marker Ki67 as a Stratification Index of Adjuvant Chemotherapy for Resectable Mucosal Melanoma
Authors: Tang Lirui , Wei Xiaoting , Li Caili , Dai Jie , Bai Xue , Mao Lili , Chi Zhihong , Cui Chuanliang , Lian Bin , Tang Bixia , Du Yu , Wang Xuan , Lai Yumei , Sheng Xinan , Yan Xieqiao , Li Siming , Zhou Li , Kong Yan , Li Zhongwu , Si Lu , Guo Jun
Published: June 2022

Background

Adjuvant chemotherapy has been shown to produce a favorable prognosis for patients with resectable mucosal melanoma (MM), resulting in the need for stratification to optimally select patients to benefit from adjuvant therapy. This study analyzed Ki67 as a potential stratification index for adjuvant chemotherapy in resectable MM.

Methods

Patients with resected MM who received subsequent adjuvant therapy in Beijing Cancer Hospital between 2010 and 2018 were retrospectively enrolled and analyzed. Relapse-free survival (RFS) and melanoma-specific survival (MSS) curves were used to perform the survival comparisons across different subgroups.

Results

From Jan 2010 to Dec 2018, 1106 MM patients were screened from a database of 4706 patients and 175 of these patients were finally enrolled. A total of 100 patients received temozolomide (TMZ)-based adjuvant chemotherapy and 75 patients received high-dose interferon-α2b (HDI) adjuvant therapy. Compared with HDI, patients who received TMZ-based adjuvant chemotherapy had significantly superior RFS (21.0 vs. 9.6 months, P = 0.002). For patients with low Ki67 expression (<30%), the two regimens showed no significant difference for impact on RFS (33.9 vs. 22.7 months, P = 0.329). However, for patients with high Ki67 expression (≥30%), TMZ-based adjuvant chemotherapy achieved favorable RFS compared with HDI (18.0 vs. 6.7 months, P < 0.001) and tended to improve MSS compared to HDI (41.4 vs. 25.1 months, P = 0.067).

Conclusion

Compared with HDI, adjuvant chemotherapy may be more relevant for patients with Ki67 ≥ 30%. Ki67 may serve as a potential index to distinguish populations benefiting from adjuvant chemotherapy in resectable MM, and may provide a basis for stratification in the selection of adjuvant regimens.
Mouse Models of Hepatocellular Carcinoma: Classification, Advancement, and Application
Authors: Liu Sha , Huang Fang , Ru Guoqing , Wang Yigang , Zhang Bixiang , Chen Xiaoping , Chu Liang
Published: June 2022

Hepatocellular carcinoma (HCC) is the subtype of liver cancer with the highest incidence, which is a heterogeneous malignancy with increasing incidence rate and high mortality. For ethical reasons, it is essential to validate medical clinical trials for HCC in animal models before further consideration on humans. Therefore, appropriate models for the study of the pathogenesis of the disease and related treatment methods are necessary. For tumor research, mouse models are the most commonly used and effective in vivo model, which is closer to the real-life environment, and the repeated experiments performed on it are closer to the real situation. Several mouse models of HCC have been developed with different mouse strains, cell lines, tumor sites, and tumor formation methods. In this review, we mainly introduce some mouse HCC models, including induced model, gene-edited model, HCC transplantation model, and other mouse HCC models, and discuss how to choose the appropriate model according to the purpose of the experiments.
Extracellular Hsp90α Supports the ePKM2-GRP78-AKT Axis to Promote Tumor Metastasis
Authors: Zhang Shaosen , Wang Caihong , Ju Jiujun , Wang Caixia
Published: June 2022

Tumor-secreted proteins can provide numerous molecular targets for cancer diagnosis and treatment. Of note, pyruvate kinase M2 (PKM2) is secreted by tumor cells to promote malignant progression, while its regulatory mechanism or the interacting network remains uncovered. In the present study, we identified extracellular heat shock protein 90 alpha (eHsp90α) as one potential interacting protein of ePKM2 by mass spectrometry (MS), which was further verified by pull-down and co-immunoprecipitation analysis. Later, we found that eHsp90α enhanced the effect of ePKM2 on migration and invasion of lung cancer cells. Blocking of Hsp90α activity, on the other hand, attenuated tumor migration or invasion induced by ePKM2. Eventually, the in vivo role of Hsp90α in regulating ePKM2 activity was validated by the mouse xenograft tumor model. Mechanistically, we found that eHsp90α binds to and stabilizes ePKM2 to protect it from degradation in the extracellular environment. Besides, eHsp90α promoted the interaction of ePKM2 with cell surface receptor GRP78, which leads to the activation of the ePKM2/GRP78/AKT axis. Collectively, we unraveled the novel molecular mechanism of eHsp90α in regulating ePKM2 activity during tumor progression, which is beneficial for the development of new treatments against lung cancer.
A Narrative Review of Preventive Central Lymph Node Dissection in Patients With Papillary Thyroid Cancer - A Necessity or an Excess
Authors: Dolidze David D. , Shabunin Alexey V. , Mumladze Robert B. , Vardanyan Arshak V. , Covantsev Serghei D. , Shulutko Alexander M. , Semikov Vasiliy I. , Isaev Khalid M. , Kazaryan Airazat M.
Published: June 2022

Objective

This review article summarises the latest evidence for preventive central lymph node dissection in patients with papillary thyroid cancer taking into account the possible complications and risk of recurrence.

Background

Papillary thyroid cancer is the most frequent histological variant of malignant neoplasms of the thyroid gland. It accounts for about 80-85% of all cases of thyroid cancer. Despite good postoperative results and an excellent survival rate in comparison with many other malignant diseases, tumor metastases to the cervical lymph nodes are frequent. Most researchers agree that the presence of obvious metastases in the lymph nodes requires careful lymph node dissection. It was suggested to perform preventive routine lymphadenectomy in all patients with malignant thyroid diseases referred to surgery.

Methods

It was performed the literature review using the “papillary thyroid cancer”, “central lymph node dissection”, “hypocalcemia”, “recurrent laryngeal nerve paresis”, “metastasis”, “cancer recurrence” along with the MESH terms. The reference list of the articles was carefully reviewed as a potential source of information. The search was based on Medline, Scopus, Google Scholar, eLibrary engines. Selected publications were analyzed and their synthesis was used to write the review and analyse the role of preventive central lymph node dissection in patients with papillary thyroid cancer.

Conclusions

The necessity of preventive central lymph node dissection in patients with differentiated papillary thyroid carcinoma is still controversial. There is much evidence that it increases the frequency of transient hypocalcemia. Due to the fact that this complication is temporary, its significance in clinical practice is debatable. It can also be assumed that an extant of surgery in the neck area is associated with an increased risk of recurrent laryngeal nerve injury. However, most studies indicate that this injury is associated more with thyroidectomy itself than with lymph node dissection. Recurrent laryngeal nerve dysfunction is also a temporary complication in the vast majority of cases. At the same time, a large amount of data shows that central lymph node dissection reduces the risk of thyroid cancer recurrence in two times.