bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic Disturbances Induced by Sleep Restriction as Potential Triggers for Alzheimer’s Disease
Authors: García-Aviles Jesús Enrique , Méndez-Hernández Rebeca , Guzmán-Ruiz Mara A. , Cruz Miguel , Guerrero-Vargas Natalí N. , Velázquez-Moctezuma Javier , Hurtado-Alvarado Gabriela
Published: September 2021

Sleep has a major role in learning, memory consolidation, and metabolic function. Although it is known that sleep restriction increases the accumulation of amyloid β peptide (Aβ) and the risk to develop Alzheimer’s disease (AD), the mechanism behind these effects remains unknown. In this review, we discuss how chronic sleep restriction induces metabolic and cognitive impairments that could result in the development of AD in late life. Here, we integrate evidence regarding mechanisms whereby metabolic signaling becomes disturbed after short or chronic sleep restriction in the context of cognitive impairment, particularly in the accumulation of Aβ in the brain. We also discuss the role of the blood-brain barrier in sleep restriction with an emphasis on the transport of metabolic signals into the brain and Aβ clearance. This review presents the unexplored possibility that the alteration of peripheral metabolic signals induced by sleep restriction, especially insulin resistance, is responsible for cognitive deficit and, subsequently, implicated in AD development.
Period 2: A Regulator of Multiple Tissue-Specific Circadian Functions
Authors: Ruggiero Gennaro , Ben-Moshe Livne Zohar , Wexler Yair , Geyer Nathalie , Vallone Daniela , Gothilf Yoav , Foulkes Nicholas S.
Published: September 2021

The zebrafish represents a powerful model for exploring how light regulates the circadian clock due to the direct light sensitivity of its peripheral clocks, a property that is retained even in organ cultures as well as zebrafish-derived cell lines. Light-inducible expression of the per2 clock gene has been predicted to play a vital function in relaying light information to the core circadian clock mechanism in many organisms, including zebrafish. To directly test the contribution of per2 to circadian clock function in zebrafish, we have generated a loss-of-function per2 gene mutation. Our results reveal a tissue-specific role for the per2 gene in maintaining rhythmic expression of circadian clock genes, as well as clock-controlled genes, and an impact on the rhythmic behavior of intact zebrafish larvae. Furthermore, we demonstrate that disruption of the per2 gene impacts on the circadian regulation of the cell cycle in vivo. Based on these results, we hypothesize that in addition to serving as a central element of the light input pathway to the circadian clock, per2 acts as circadian regulator of tissue-specific physiological functions in zebrafish.
Sustained Baclofen-Induced Activation of GABAB Receptors After Cerebral Ischemia Restores Receptor Expression and Function and Limits Progressing Loss of Neurons
Authors: Hleihil Mohammad , Vaas Markus , Bhat Musadiq A. , Balakrishnan Karthik , Benke Dietmar
Published: September 2021

One important function of GABAB receptors is the control of neuronal activity to prevent overexcitation and thereby excitotoxic death, which is a hallmark of cerebral ischemia. Consequently, sustained activation of GABAB receptors with the selective agonist baclofen provides neuroprotection in in vitro and in vivo models of cerebral ischemia. However, excitotoxic conditions severely downregulate the receptors, which would compromise the neuroprotective effectiveness of baclofen. On the other hand, recent work suggests that sustained activation of GABAB receptors stabilizes receptor expression. Therefore, we addressed the question whether sustained activation of GABAB receptors reduces downregulation of the receptor under excitotoxic conditions and thereby preserves GABAB receptor-mediated inhibition. In cultured neurons subjected to oxygen and glucose deprivation (OGD), to mimic cerebral ischemia, GABAB receptors were severely downregulated. Treatment of the cultures with baclofen after OGD restored GABAB receptor expression and reduced loss of neurons. Restoration of GABAB receptors was due to enhanced fast recycling of the receptors, which reduced OGD-induced sorting of the receptors to lysosomal degradation. Utilizing the middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia, we verified the severe downregulation of GABAB receptors in the affected cortex and a partial restoration of the receptors after systemic injection of baclofen. Restored receptor expression recovered GABAB receptor-mediated currents, normalized the enhanced neuronal excitability observed after MCAO and limited progressive loss of neurons. These results suggest that baclofen-induced restoration of GABAB receptors provides the basis for the neuroprotective activity of baclofen after an ischemic insult. Since GABAB receptors regulate multiple beneficial pathways, they are promising targets for a neuroprotective strategy in acute cerebral ischemia.
Distinctive Regulation of Emotional Behaviors and Fear-Related Gene Expression Responses in Two Extended Amygdala Subnuclei With Similar Molecular Profiles
Authors: Ueda Shuhei , Hosokawa Masahito , Arikawa Koji , Takahashi Kiyofumi , Fujiwara Mao , Kakita Manami , Fukada Taro , Koyama Hiroaki , Horigane Shin-ichiro , Itoi Keiichi , Kakeyama Masaki , Matsunaga Hiroko , Takeyama Haruko , Bito Haruhiko , Takemoto-Kimura Sayaka
Published: September 2021

The central nucleus of the amygdala (CeA) and the lateral division of the bed nucleus of the stria terminalis (BNST) are the two major nuclei of the central extended amygdala that plays essential roles in threat processing, responsible for emotional states such as fear and anxiety. While some studies suggested functional differences between these nuclei, others showed anatomical and neurochemical similarities. Despite their complex subnuclear organization, subnuclei-specific functional impact on behavior and their underlying molecular profiles remain obscure. We here constitutively inhibited neurotransmission of protein kinase C-δ-positive (PKCδ+) neurons—a major cell type of the lateral subdivision of the CeA (CeL) and the oval nucleus of the BNST (BNSTov)—and found striking subnuclei-specific effects on fear- and anxiety-related behaviors, respectively. To obtain molecular clues for this dissociation, we conducted RNA sequencing in subnuclei-targeted micropunch samples. The CeL and the BNSTov displayed similar gene expression profiles at the basal level; however, both displayed differential gene expression when animals were exposed to fear-related stimuli, with a more robust expression change in the CeL. These findings provide novel insights into the molecular makeup and differential engagement of distinct subnuclei of the extended amygdala, critical for regulation of threat processing.
Patient-Specific Network Connectivity Combined With a Next Generation Neural Mass Model to Test Clinical Hypothesis of Seizure Propagation
Authors: Gerster Moritz , Taher Halgurd , Škoch Antonín , Hlinka Jaroslav , Guye Maxime , Bartolomei Fabrice , Jirsa Viktor , Zakharova Anna , Olmi Simona
Published: September 2021

Dynamics underlying epileptic seizures span multiple scales in space and time, therefore, understanding seizure mechanisms requires identifying the relations between seizure components within and across these scales, together with the analysis of their dynamical repertoire. In this view, mathematical models have been developed, ranging from single neuron to neural population. In this study, we consider a neural mass model able to exactly reproduce the dynamics of heterogeneous spiking neural networks. We combine mathematical modeling with structural information from non invasive brain imaging, thus building large-scale brain network models to explore emergent dynamics and test the clinical hypothesis. We provide a comprehensive study on the effect of external drives on neuronal networks exhibiting multistability, in order to investigate the role played by the neuroanatomical connectivity matrices in shaping the emergent dynamics. In particular, we systematically investigate the conditions under which the network displays a transition from a low activity regime to a high activity state, which we identify with a seizure-like event. This approach allows us to study the biophysical parameters and variables leading to multiple recruitment events at the network level. We further exploit topological network measures in order to explain the differences and the analogies among the subjects and their brain regions, in showing recruitment events at different parameter values. We demonstrate, along with the example of diffusion-weighted magnetic resonance imaging (dMRI) connectomes of 20 healthy subjects and 15 epileptic patients, that individual variations in structural connectivity, when linked with mathematical dynamic models, have the capacity to explain changes in spatiotemporal organization of brain dynamics, as observed in network-based brain disorders. In particular, for epileptic patients, by means of the integration of the clinical hypotheses on the epileptogenic zone (EZ), i.e., the local network where highly synchronous seizures originate, we have identified the sequence of recruitment events and discussed their links with the topological properties of the specific connectomes. The predictions made on the basis of the implemented set of exact mean-field equations turn out to be in line with the clinical pre-surgical evaluation on recruited secondary networks.
Acute Corticotropin-Releasing Factor Receptor Type 2 Agonism Results in Sustained Symptom Improvement in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Authors: Pereira Gerard , Gillies Hunter , Chanda Sanjay , Corbett Michael , Vernon Suzanne D. , Milani Tina , Bateman Lucinda
Published: September 2021

Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multi-symptom disease with widespread evidence of disrupted systems. The authors hypothesize that it is caused by the upregulation of the corticotropin-releasing factor receptor type 2 (CRFR2) in the raphé nuclei and limbic system, which impairs the ability to maintain homeostasis. The authors propose utilizing agonist-mediated receptor endocytosis to downregulate CRFR2.

Materials and Methods

This open-label trial tested the safety, tolerability and efficacy of an acute dose of CT38s (a short-lived, CRFR2-selective agonist, with no known off-target activity) in 14 ME/CFS patients. CT38s was subcutaneously-infused at one of four dose-levels (i.e., infusion rates of 0.01, 0.03, 0.06, and 0.20 μg/kg/h), for a maximum of 10.5 h. Effect was measured as the pre-/post-treatment change in the mean 28-day total daily symptom score (TDSS), which aggregated 13 individual patient-reported symptoms.

Results

ME/CFS patients were significantly more sensitive to the transient hemodynamic effects of CRFR2 stimulation than healthy subjects in a prior trial, supporting the hypothesized CRFR2 upregulation. Adverse events were generally mild, resolved without intervention, and difficult to distinguish from ME/CFS symptoms, supporting a CRFR2 role in the disease. The acute dose of CT38s was associated with an improvement in mean TDSS that was sustained (over at least 28 days post-treatment) and correlated with both total exposure and pre-treatment symptom severity. At an infusion rate of 0.03 μg/kg/h, mean TDSS improved by −7.5 ± 1.9 (or −25.7%, p = 0.009), with all monitored symptoms improving.

Conclusion

The trial supports the hypothesis that CRFR2 is upregulated in ME/CFS, and that acute CRFR2 agonism may be a viable treatment approach warranting further study.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT03613129.
LC-Q-Orbitrap-MS/MS Characterization, Antioxidant Activity, and α-Glucosidase-Inhibiting Activity With In Silico Analysis of Extract From Clausena Indica (Datz.) Oliv Fruit Pericarps
Authors: Wang Ruimin , He Ruiping , Li Zhaohui , Wang Lu
Published: September 2021

Clausena indica (Datz.) Oliv fruit pericarps (CIOPs) is an important agro-industrial by-product rich in active components. In this article, the effects of traditional and green deep eutectic solvents (DESs) on the high-performance liquid chromatography (HPLC) characterization, antioxidant activities, and α-glucosidase-inhibitory activity of phenolic extracts from CIOPs were investigated for the first time. The results showed that ChCl-Gly and Bet-CA had higher extraction efficiency for the total phenolic content (TPC, 64.14–64.83 mg GAE/g DW) and total flavonoid content (TFC, 47.83–48.11 mg RE/g DW) compared with the traditional solvents (water, methanol, and ethyl acetate). LC-Q-Orbitrap-MS/MS was adopted to identify the phenolic compositions of the CIOPs extracts. HPLC-diode array detection (HPLC-DAD) results indicated that arbutin, (–)-epigallocatechin, chlorogenic acid, procyanidin B1, (+)-catechin, and (–)-epicatechin were the major components for all extracts, especially for deep eutectic solvents (DESs). In addition, ChCl-Xyl and ChCl-Gly extracts showed higher antioxidant activities against 2,2-diphenyl-1-picrylhydrazyl (DPPH•), 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid (ABTS+•), ferric reducing antioxidant power (FRAP), reducing power (RP), and cupric ion reducing antioxidant capacity (CUPRAC) than extracts extracted by other solvents. A strong α-glucosidase-inhibiting activity (IC50, 156.25-291.11 μg/ml) was found in three DESs extracts. Furthermore, in silico analysis of the major phenolics in the CIOPs extracts was carried out to explore their interactions with α-glucosidase. Multivariate analysis was carried out to determine the key factors affecting the antioxidant activity and α-glucosidase-inhibiting activity. In short, DES can be taken as a promising solvent for valorization and recovery of bioactive compounds from agro-industrial by-products. The results verified that CIOPs can be used as a prospective source rich in bio-active compounds applied in the food and pharmacy industries.
Effects of Different Combinations of Sugar and Starch Concentrations on Ruminal Fermentation and Bacterial-Community Composition in vitro
Authors: Dong Jia-nan , Li Song-ze , Chen Xue , Qin Gui-xin , Wang Tao , Sun Zhe , Wu Di , Zhao Wei , Demelash Natnael , Zhang Xue-feng , Zhen Yu-guo
Published: September 2021

High levels of starch is known to have positive effects on both energy supply and milk yield but increases the risk of rumen acidosis. The use of sugar as a non-structural carbohydrate could circumvent this risk while maintaining the benefits, but its effects and that of the simultaneous use of both sugar and starch are not as well-understood. This study aimed to evaluate the effects of different combinations of sugar and starch concentrations on ruminal fermentation and bacterial community composition in vitro in a 4 ×4 factorial experiment. Sixteen dietary treatments were formulated with 4 levels of sugar (6, 8, 10, and 12% of dietary dry matter), and 4 levels of starch (21, 23, 25, and 27% of dietary dry matter). Samples were taken at 0.5, 1, 3, 6, 12, and 24 h after cultivation to determine the disappearance rate of dry matter, rumen fermentation parameters and bacterial community composition. Butyric acid, gas production, and Treponema abundance were significantly influenced by the sugar level. The pH, acetic acid, and propionic acid levels were significantly influenced by starch levels. However, the interactive effect of sugar and starch was only observed on the rate of dry matter disappearance. Furthermore, different combinations of starch and sugar had different effects on volatile fatty acid production rate, gas production rate, and dry matter disappearance rate. The production rate of rumen fermentation parameters in the high sugar group was higher. Additionally, increasing the sugar content in the diet did not change the main phylum composition in the rumen, but significantly increased the relative abundance of Bacteroidetes and Firmicutes phyla, while the relative abundance of Proteobacteria was reduced. At the genus level, the high glucose group showed significantly higher relative abundance of Treponema (P < 0.05) and significantly lower relative abundance of Ruminobacter, Ruminococcus, and Streptococcus (P < 0.05). In conclusion, different combinations of sugar and starch concentrations have inconsistent effects on rumen fermentation characteristics, suggesting that the starch in diets cannot be simply replaced with sugar; the combined effects of sugar and starch should be considered to improve the feed utilization rate.
A Comparative Study of Two In Vivo PET Verification Methods in Clinical Cases
Authors: Zhang Junyu , Lu Yan , Sheng Yinxiangzi , Wang Weiwei , Hong Zhengshan , Sun Yun , Zhou Rong , Cheng Jingyi
Published: September 2021

Purpose

Positron emission tomography (PET) range verification is an important method that can help improve the confidence in proton therapy for clinical applications. Two kinds of verification methods are implemented and compared based on clinical cases in this study.

Method

The study is conducted on 14 breast cancer patients following proton irradiation treatment. Verification is done by calculating the depth error between the numerically predicted values with the measured PET image along the beam direction. Point-based and segment-based methods are applied and compared. The verification results are presented as depth error means and standard deviations in a region of interest (ROI).

Results

The mean value of the depth error of all 14 cases is within the range of [−3, 3] mm for both point-based and segment-based methods, and only one case result calculated by the point-based method is slightly beyond −3 mm. When comparing the mean depth error from the two methods, the paired t-test result shows that the p-value is 0.541, and the standard deviation of the segment-based method is smaller than that of the point-based method.

Conclusion

In breast cancer case verification application, point-based and segment-based methods show no significant difference in the mean value of results. Both methods can quantify the accuracy of proton radiotherapy to the millimeter level.
Appropriate PD-L1 Cutoff Value for Gastric Cancer Immunotherapy: A Systematic Review and Meta-Analysis
Authors: Xie Tong , Zhang Zhening , Zhang Xiaotian , Qi Changsong , Shen Lin , Peng Zhi
Published: September 2021

Background

Immunotherapy dramatically changed the treatment landscape of gastric cancer in recent years. PD-L1 expression was proposed as a biomarker; however, the treatment strategy according to PD-L1 is still uncertain. Here, we aimed to find the appropriate cutoff value of PD-L1 expression for gastric cancer immunotherapy.

Methods

We did a systematic electronic research of prospective clinical trials of gastric cancer immunotherapy across databases. Studies that provided subgroup analysis results stratified by PD-L1 expression were included. Objective response rate (ORR), disease control rate (DCR), hazard ratio (HR), and 95% confidential interval (CI) of progression-free survival (PFS) and overall survival (OS) at different PD-L1 cutoff values were extracted.

Results

Twelve studies and 6,488 patients in total were finally included for pooled analysis. ORR in allover, PD-L1-negative, combined positive score (CPS) ≥1, CPS ≥5, and CPS ≥10 population was 10%, 3%, 13%, 20%, and 23%, respectively. Immune checkpoint inhibitor (ICI) monotherapy failed to show survival advantage in allover and PD-L1-negative patients. Single-agent ICI therapy prolonged OS (HR = 0.84, 95% CI: 0.74–0.96) but not PFS (HR = 1.38, 95% CI: 0.91–2.09) in PD-L1 CPS ≥1 patients. For combined immunotherapy, ORR in allover, PD-L1-negative, CPS ≥1, CPS ≥5, and CPS ≥10 population was 64%, 57%, 48%, 60%, and 58%, respectively. Allover population could gain survival benefit from combined immunotherapy based on the results from Checkmate-649. OS (HR = 0.81, 95% CI: 0.71–0.92) and PFS (HR = 0.77, 95% CI: 0.69–0.86) were significantly prolonged in PD-L1 CPS ≥1 patients receiving combined immunotherapy.

Conclusion

Efficacy and survival advantages improved with PD-L1 CPS. CPS ≥1 was the cutoff value for ICI monotherapy to gain survival benefit. Combined immunotherapy prolonged PFS and OS in allover population but needs further study to confirm it.
Development and Validation of a Novel Model for Predicting Prognosis of Non-PCR Patients After Neoadjuvant Therapy for Breast Cancer
Authors: Yu Yongqiang , Wu Si , Xing Hui , Han Mengxue , Li Jinze , Liu Yueping
Published: September 2021

Purpose

Pathologic complete response (pCR) after neoadjuvant therapy is an important indicator of long-term prognosis and the primary endpoint of many neoadjuvant studies. For breast cancer patients who do not achieve pCR, prognostic indicators related to prognosis are particularly important. This study is constructing a prediction model with more accurate and reliable prediction results by combining multiple clinicopathological factors, so as to provide a more accurate decision-making basis for subsequent clinical treatment.

Patients and Methods

In this study, 1,009 cases of invasive breast cancer and surgically resected after neoadjuvant therapy from 2010 to 2017. All indicators in this trial were interpreted in a double-blind manner by two pathologists with at least 10 years of experience, including histological grading, Tils, ER, PR, HER2, and Ki67. The prediction model used R language to calculate the calibration degree and ROC curve of the prediction model in the training set and validation set.

Results

Through univariate survival analysis, the results showed histological grade (P=0.037), clinical stage (P<0.001), HER2 (P=0.044), RCB class (P<0.001), Tils (P<0.001), lymph node status (P =0.049), MP grade (P=0.013) are related to OS in non-PCR patients after neoadjuvant. Data were analyzed by substituting in a multivariate analysis, and the results were that clinical stage, HER2, RCB grading, and Tils grading were correlated with OS in non-PCR patients after neoadjuvant therapy for breast cancer. Among all cases in the training set, the prediction model predicted that the 3-year survival AUC value was 0.95 and 5-year survival AUC value was 0.79, and the RCB classification of 3-year survival and 5-year survival were 0.70 and 0.67, respectively, which proved that the prediction model could predict the OS of non-PCR patients after neoadjuvant therapy for breast cancer more accurately than the RCB classification, and showed the same results in HR, HER2+, and TN classifications. It also showed the same results in validation set.

Conclusion

These data indicate that the predicted values of the prediction model developed in this study match the actual survival rates without underestimating the mortality risk and have a relatively accurate prediction effect.
A Radiomics Model for Predicting Early Recurrence in Grade II Gliomas Based on Preoperative Multiparametric Magnetic Resonance Imaging
Authors: Wang Zhen-hua , Xiao Xin-Lan , Zhang Zhao-Tao , He Keng , Hu Feng
Published: September 2021

Objective

This study aimed to develop a radiomics model to predict early recurrence (<1 year) in grade II glioma after the first resection.

Methods

The pathological, clinical, and magnetic resonance imaging (MRI) data of patients diagnosed with grade II glioma who underwent surgery and had a recurrence between 2017 and 2020 in our hospital were retrospectively analyzed. After a rigorous selection, 64 patients were eligible and enrolled in the study. Twenty-two cases had a pathologically confirmed recurrent glioma. The cases were randomly assigned using a ratio of 7:3 to either the training set or validation set. T1-weighted image (T1WI), T2-weighted image (T2WI), and contrast-enhanced T1-weighted image (T1CE) were acquired. The minimum-redundancy-maximum-relevancy (mRMR) method alone or in combination with univariate logistic analysis were used to identify the most optimal predictive feature from the three image sequences. Multivariate logistic regression analysis was then used to develop a predictive model using the screened features. The performance of each model in both training and validation datasets was assessed using a receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA).

Results

A total of 396 radiomics features were initially extracted from each image sequence. After running the mRMR and univariate logistic analysis, nine predictive features were identified and used to build the multiparametric radiomics model. The model had a higher AUC when compared with the univariate models in both training and validation data sets with an AUC of 0.966 (95% confidence interval: 0.949–0.99) and 0.930 (95% confidence interval: 0.905–0.973), respectively. The calibration curves indicated a good agreement between the predictable and the actual probability of developing recurrence. The DCA demonstrated that the predictive value of the model improved when combining the three MRI sequences.

Conclusion

Our multiparametric radiomics model could be used as an efficient and accurate tool for predicting the recurrence of grade II glioma.
The Role of Exosomal miRNAs in Glioma: Biological Function and Clinical Application
Authors: Aili Yirizhati , Maimaitiming Nuersimanguli , Mahemuti Yusufu , Qin Hu , Wang Yongxin , Wang Zengliang
Published: September 2021

Gliomas are complex and heterogeneous central nervous system tumors with poor prognosis. Despite the increasing development of aggressive combination therapies, the prognosis of glioma is generally unsatisfactory. Exosomal microRNA (miRNA) has been successfully used in other diseases as a reliable biomarker and even therapeutic target. Recent studies show that exosomal miRNA plays an important role in glioma occurrence, development, invasion, metastasis, and treatment resistance. However, the association of exosomal miRNA between glioma has not been systemically characterized. This will provide a theoretical basis for us to further explore the relationship between exosomal miRNAs and glioma and also has a positive clinical significance in the innovative diagnosis and treatment of glioma.
Two-Trait Predictor of Venous Invasion on Contrast-Enhanced CT as a Preoperative Predictor of Outcomes for Early-Stage Hepatocellular Carcinoma After Hepatectomy
Authors: Li Xinming , Zhang Xuchang , Li Zhipeng , Xie Chuanmiao , Qin Shuping , Yan Meng , Ke Qiying , Jin Xuan , Lin Ting , Zhou Muyao , Liang Wen , Qi Zhendong , Geng Zhijun , Quan Xianyue
Published: September 2021

Objectives

This study aimed to assess the effectiveness of the two-trait predictor of venous invasion (TTPVI) on contrast-enhanced computed tomography (CECT) for the preoperative prediction of clinical outcomes in patients with early-stage hepatocellular carcinoma (HCC) after hepatectomy.

Methods

This retrospective study included 280 patients with surgically resected HCC who underwent preoperative CECT between 2012 and 2013. CT imaging features of HCC were assessed, and univariate and multivariate Cox regression analyses were used to evaluate the CT features associated with disease-free survival (DFS) and overall survival (OS). Subgroup analyses were used to summarized the hazard ratios (HRs) between patients in whom TTPVI was present and those in whom TTPVI was absent using a forest plot.

Results

Capsule appearance [HR, 0.504; 95% confidence interval (CI), 0.341–0.745; p < 0.001], TTPVI (HR, 1.842; 95% CI, 1.319–2.572; p < 0.001) and high level of alanine aminotransferase (HR, 1.620; 95% CI, 1.180–2.225, p = 0.003) were independent risk factors for DFS, and TTPVI (HR, 2.509; 95% CI, 1.518–4.147; p < 0.001), high level of alpha-fetoprotein (HR, 1.722; 95% CI, 1.067–2.788; p = 0.026), and gamma-glutamyl transpeptidase (HR, 1.787; 95% CI, 1.134–2.814; p = 0.026) were independent risk factors for OS. A forest plot revealed that the TTPVI present group had lower DFS and OS rates in most subgroups. Patients in whom TTPVI was present in stages I and II had a lower DFS and OS than those in whom TTPVI was absent. Moreover, there were significant differences in DFS (p < 0.001) and OS (p < 0.001) between patients classified as Barcelona Clinic Liver Cancer stage A in whom TTPVI was absent and in whom TTPVI was present.

Conclusions

TTPVI may be used as a preoperative biomarker for predicting postoperative outcomes for patients with early-stage HCC.
RETRACTED: MiR-1236-3p Inhibits the Proliferation, Invasion, and Migration of Colon Cancer Cells and Hinders Epithelial-Mesenchymal Transition by Targeting DCLK3
Authors: Zhao Yibin , Zhou Hongyi , Shen Jie , Yang Shaohui , Deng Ke , Li Qi , Cui Wei
Published: September 2021

Background

Dysregulated microRNAs (miRNAs) are common in human cancer and are involved in the proliferation, promotion, and metastasis of tumor cells. Therefore, this study aimed to evaluate the expression and biological function of miR-1236-3p in colon cancer.

Methods

This study screened the miRNA in normal and colon cancer tissues through array analysis. In addition, quantitative Reverse Transcription–Polymerase Chain Reaction (qRT-PCR) analysis was performed to validate the expression of miR-1236-3p in normal and tumor tissues from colon cancer patients and cancer cell lines. Online predicting algorithms and luciferase reporter assays were also employed to confirm Doublecortin Like Kinase 3 (DCLK3) was the target for miR-1236-3p. Moreover, the impact of miR-1236-3p on the progression of colon cancer was evaluated in vitro and in vivo. Western blotting and qRT-PCR were also performed to investigate the interactions between miR-1236-3p and DCLK3.

Results

MiR-1236-3p was significantly downregulated in colon cancer tissues and its expression was associated with the TNM stage and metastasis of colon. In addition, the in vitro and in vivo experiments showed that miR-1236-3p significantly promoted cancer cell apoptosis and inhibited the proliferation, invasion, and migration of cancer cells. The results also showed that miR-1236-3p hindered Epithelial–mesenchymal Transition (EMT) by targeting DCLK3. Moreover, the expression of DCLK3 mediated the effects of miR-1236-3p on the progression of cancer.

Conclusions

MiR-1236-3p functions as a tumor suppressor in colon cancer by targeting DCLK3 and is therefore a promising therapeutic target for colon cancer.
The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer
Authors: Liu Chang , Jin Ying , Fan Zhimin
Published: September 2021

Although chemotherapy can improve the overall survival and prognosis of cancer patients, chemoresistance remains an obstacle due to the diversity, heterogeneity, and adaptability to environmental alters in clinic. To determine more possibilities for cancer therapy, recent studies have begun to explore changes in the metabolism, especially glycolysis. The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically, even under normoxia, which contributes to chemoresistance. However, the association between glycolysis and chemoresistance and molecular mechanisms of glycolysis-induced chemoresistance remains unclear. This review describes the mechanism of glycolysis-induced chemoresistance from the aspects of glycolysis process, signaling pathways, tumor microenvironment, and their interactions. The understanding of how glycolysis induces chemoresistance may provide new molecular targets and concepts for cancer therapy.
Prognostic Value of NLRP3 Inflammasome and TLR4 Expression in Breast Cancer Patients
Authors: Saponaro Concetta , Scarpi Emanuela , Sonnessa Margherita , Cioffi Antonella , Buccino Francesca , Giotta Francesco , Pastena Maria Irene , Zito Francesco Alfredo , Mangia Anita
Published: September 2021

Inflammasome complexes play a pivotal role in different cancer types. NOD-like receptor protein 3 (NLRP3) inflammasome is one of the most well-studied inflammasomes. Activation of the NLRP3 inflammasome induces abnormal secretion of soluble cytokines, generating advantageous inflammatory surroundings that support tumor growth. The expression levels of the NLRP3, PYCARD and TLR4 were determined by immunohistochemistry in a cohort of primary invasive breast carcinomas (BCs). We observed different NLRP3 and PYCARD expressions in non-tumor vs tumor areas (p<0.0001). All the proteins were associated to more aggressive clinicopathological characteristics (tumor size, grade, tumor proliferative activity etc.). Univariate analyses were carried out and related Kaplan-Meier curves plotted for NLRP3, PYCARD and TLR4 expression. Patients with higher NLRP3 and TLR4 expression had worse 5-year disease-free survival (DFS) compared to patients with lower NLRP3 and TLR4 expression (p =0.021 and p = 0.009, respectively). In multivariate analysis, TLR4 was confirmed as independent prognostic factors for DFS (HR = 2.03, 95% CI 1.16–3.57, p = 0.014), and high NLRP3 expression showed a slight association with DFS (HR = 1.75, 95% CI 0.98–3.15, p = 0.06). In conclusion, we showed TLR4 expression as independent prognostic factors and we highlighted for the first time that high expression of NLRP3 is linked to a poor prognosis in BC patients. These results suggest that NLRP3 and TLR4 could be two new good prognostic factor for BC patients.
Establishing ADC-Based Histogram and Texture Features for Early Treatment-Induced Changes in Head and Neck Squamous Cell Carcinoma
Authors: Rodrigues Anna , Loman Kelly , Nawrocki Jeff , Hoang Jenny K. , Chang Zheng , Mowery Yvonne M. , Oyekunle Taofik , Niedzwiecki Donna , Brizel David M. , Craciunescu Oana
Published: September 2021

The purpose of this study was to assess baseline variability in histogram and texture features derived from apparent diffusion coefficient (ADC) maps from diffusion-weighted MRI (DW-MRI) examinations and to identify early treatment-induced changes to these features in patients with head and neck squamous cell carcinoma (HNSCC) undergoing definitive chemoradiation. Patients with American Joint Committee on Cancer Stage III–IV (7th edition) HNSCC were prospectively enrolled on an IRB-approved study to undergo two pre-treatment baseline DW-MRI examinations, performed 1 week apart, and a third early intra-treatment DW-MRI examination during the second week of chemoradiation. Forty texture and six histogram features were derived from ADC maps. Repeatability of the features from the baseline ADC maps was assessed with the intra-class correlation coefficient (ICC). A Wilcoxon signed-rank test compared average baseline and early treatment feature changes. Data from nine patients were used for this study. Comparison of the two baseline ADC maps yielded 11 features with an ICC ≥ 0.80, indicating that these features had excellent repeatability: Run Gray-Level Non-Uniformity, Coarseness, Long Zone High Gray-Level, Variance (Histogram Feature), Cluster Shade, Long Zone, Variance (Texture Feature), Run Length Non-Uniformity, Correlation, Cluster Tendency, and ADC Median. The Wilcoxon signed-rank test resulted in four features with significantly different early treatment-induced changes compared to the baseline values: Run Gray-Level Non-Uniformity (p = 0.005), Run Length Non-Uniformity (p = 0.005), Coarseness (p = 0.006), and Variance (Histogram) (p = 0.006). The feasibility of histogram and texture analysis as a potential biomarker is dependent on the baseline variability of each metric, which disqualifies many features.
Efficacy of Omentum-Preserving Gastrectomy for Patients With Gastric Cancer: A Systematic Review and Meta-Analysis
Authors: Li Zonglin , Song Min , Zhou Yejiang , Jiang Huaiwu , Xu Linxia , Hu Zhengchuan , Liu Yi , Jiang Yifan , Li Xin
Published: September 2021

Background

Complete omentectomy is considered to be essential in the radical gastrectomy for gastric cancer (GC), but its clinical benefit remains unclear. This study aims to evaluate the efficacy of omentum-preserving gastrectomy (OPG) for patients with GC.

Methods

Studies comparing the surgical and oncological outcomes of OPG and gastrectomy with complete omentectomy (GCO) for GC up to March 2021 were systematically searched from PubMed, Web of Science, Embase, and Cochrane Library. A pooled analysis was performed for the available data regarding the baseline features, surgical and oncological outcomes. The RevMan 5.3 software was used to perform the statistical analysis. Quality evaluation and publication bias were also conducted.

Results

Nine studies with a total of 3335 patients (1372 in the OPG group and 1963 in the GCO group) undergoing gastrectomy were included. In the pooled analysis, the baseline data in two groups were all comparable (p > 0.05). However, the OPG group was associated with shorter operative time (MD = −18.67, 95% CI = −31.42 to −5.91, P = 0.004) and less intraoperative blood loss (MD = −38.09, 95% CI = −53.78 to −22.41, P < 0.00001) than the GCO group. However, the number of dissected lymph nodes (MD = 2.16, 95% CI = −0.61 to 4.93, P = 0.13), postoperative complications (OR = 0.92, 95% CI = 0.74 to 1.15, p = 0.47), overall recurrence rate (OR = 0.83, 95% CI = 0.66 to 1.06, p = 0.14), peritoneal recurrence rate (OR = 0.91, 95% CI = 0.65 to 1.29, p = 0.60), 3-year relapse-free survival (RFS) rate (OR = 1.40, 95% CI = 0.86 to 2.27, p = 0.18), and 5-year RFS rate (OR = 1.21, 95% CI = 0.95 to 1.55, p = 0.12) of the two groups were comparable.

Conclusions

OPG might be an oncologically safe procedure with better surgical outcomes for patients with GC than GCO. However, high-quality randomized controlled trials are needed to confirm this benefit.
Comparison of Sutureless Versus Suture Partial Nephrectomy for Clinical T1 Renal Cell Carcinoma: A Meta-Analysis of Retrospective Studies
Authors: Zhang Wenjun , Che Bangwei , Xu Shenghan , Mu Yi , He Jun , Tang Kaifa
Published: September 2021

Background

Partial nephrectomy (PN) is the recommended treatment for T1 renal cell carcinoma (RCC). Compared with suture PN, sutureless PN reduces the difficulty and time of operation, but the safety and feasibility have been controversial. This meta-analysis was conducted to compare the function and perioperative outcomes of suture and sutureless PN for T1 RCC.

Methods

Systematic literature review was performed up to April 2021 using multiple databases to identify eligible comparative studies. According to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria, identification and selection of the studies were conducted. Meta-analysis was performed for studies comparing suture to sutureless PN for both T1a and T1b RCC. In addition, subgroup analysis was performed on operation time, warm ischemia time, estimated blood loss, and postoperative complications. Sensitivity analysis was used in analysis with high heterogeneity (operation time and estimated blood loss).

Results

Eight retrospective studies were included with a total of 1,156 patients; of the 1,156 patients, 499 received sutureless PN and 707 received suture PN. The results showed that sutureless PN had shorter operative time (I2 = 0%, P < 0.001), warm ischemia time (I2 = 97.5%, P < 0.001), and lower clamping rate (I2 = 85.8%, P = 0.003), but estimated blood loss (I2 = 76.6%, P = 0.064) had no difference. In the comparison of perioperative outcomes, there was no significant difference in postoperative complications (I2 = 0%, P = 0.999), positive surgical margins (I2 = 0%, P = 0.356), postoperative estimated glomerular filtration rat (eGFR) (I2 = 0%, P = 0.656), and tumor recurrence (I2 = 0%, P = 0.531).

Conclusions

In T1a RCC with low RENAL score, sutureless PN is a feasible choice, whereas it should not be overestimated in T1b RCC.
Non-Hodgkin’s Lymphoma Presenting as Isolated Peritoneal Lymphomatosis: A Case Report and Literature Review
Authors: Zhu Min , Wu Zhixuan , Yang Zhaoxia , Ning Bo , Yu Shengjie , Gu Xiling , Yu Huihong
Published: September 2021

Peritoneal lymphomatosis is extremely rare and associated with poor prognosis. Most practitioners only pay more attention to peritoneal carcinomatosis. However, peritoneal lymphomatosis can be neglected and misdiagnosed. We report a teenager with 10 days of abdominal distension and pain accompanied by computed tomography scan suggesting diffuse thickening of the peritoneum and omentum and abdominopelvic effusion. Tuberculous peritonitis and peritoneal carcinomatosis were initially suspected. However, it was finally confirmed as non-Hodgkin’s B-cell lymphoma by omentum biopsies. He achieved complete remission after chemotherapy and autologous stem cell transplantation. But unfortunately, he suffered a relapse and died 10 months after diagnosis. Following a review of the literature, it can be concluded that the discovery of lymphomatosis in peritoneum is a rare finding. Lymphoma should be considered in the differential diagnosis of unexplained peritoneal thickening on computed tomography, and this case emphasizes the importance of early pathological diagnosis to make sure that the right treatment can be started opportunely.
The Prognostic Value of CD133 in Predicting the Relapse and Recurrence Pattern of High-Grade Gliomas on MRI: A Meta-Analysis
Authors: Abdoli Shadbad Mahdi , Hosseinkhani Negar , Asadzadeh Zahra , Brunetti Oronzo , Silvestris Nicola , Baradaran Behzad
Published: September 2021

Background

Cancer stem cells have been implicated in tumor relapse, tumor invasion, and cancer therapy resistance in high-grade gliomas; thus, characterizing cancer stem cell-related markers can help determine the prognosis of affected patients. Preclinical studies have reported that CD133 is implicated in tumor recurrence and cancer therapy resistance in high-grade gliomas; however, clinical studies have reported inconclusive results regarding its prognostic value in patients with high-grade gliomas.

Methods

We systematically searched the PubMed, Scopus, Web of Science, and Embase databases to obtain peer-reviewed studies published before March 10, 2021. Then, we conducted the current systematic review and meta-analysis based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statements. By applying the random-effect model, the effect size of studies investigating the progression-free survival (PFS), time to local recurrence (TTL), and time to distant recurrence (TTD) were calculated using RevMan version 5.4. The heterogeneity between the included studies was studied by the I2 index and Cochran’s Q test. Egger test was performed on funnel plots to investigate the potential asymmetry and publication bias among the included studies using CMA version 2.

Results

With the 10% cut-off, CD133 protein overexpression is associated with the inferior PFS of patients with high-grade gliomas. Increased CD133 protein expression is associated with sooner distant tumor recurrence on MRI in glioblastoma patients and patients with high-grade gliomas and improved TTL on MRI in glioblastoma patients.

Conclusion

Based on the current evidence from 1086 patients with high-grade gliomas, CD133 overexpression is a valuable marker to predict tumor relapse and tumor recurrence patterns in patients with high-grade gliomas.
Role of Tetraspanins in Hepatocellular Carcinoma
Authors: Cai Sicheng , Deng Yue , Peng Huiming , Shen Jian
Published: September 2021

Hepatocellular carcinoma (HCC) is characterized by high prevalence, morbidity, and mortality. Liver cancer is the sixth most common cancer worldwide; and its subtype, HCC, accounts for nearly 80% of cases. HCC progresses rapidly, and to date, there is no efficacious treatment for advanced HCC. Tetraspanins belong to a protein family characterized by four transmembrane domains. Thirty-three known tetraspanins are widely expressed on the surface of most nucleated cells and play important roles in different biological processes. In our review, we summarize the functions of tetraspanins and their underlying mechanism in the life cycle of HCC, from its initiation, progression, and finally to treatment. CD9, TSPAN15, and TSPAN31 can promote HCC cell proliferation or suppress apoptosis. CD63, CD151, and TSPAN8 can also facilitate HCC metastasis, while CD82 serves as a suppressor of metastasis. TSPAN1, TSPAN8, and CD151 act as prognosis indicators and are inversely correlated to the overall survival rate of HCC patients. In addition, we discuss the potential of role of the tetraspanin family proteins as novel therapeutic targets and as an approach to overcome drug resistance, and also provide suggestions for further research.
Activity of Wnt/PCP Regulation Pathway Classifies Patients of Low-Grade Glioma Into Molecularly Distinct Subgroups With Prognostic Difference
Authors: Zhang Meng , Wang Dan , Su Lan , Ma Jingjiao , Wang Sizhen , Cui Meng , Hong Shunming , Guan Bing , Ma Xiaodong
Published: September 2021

Wingless/Int-1 (Wnt) signaling is one of the most well-known oncogenic pathways. Numerous studies have uncovered an aberrant expression of Wnt in cancer and its association with multiple oncogenic processes, such as cell proliferation, epithelial–mesenchymal transition (EMT), and invasiveness. Most previous studies mainly focused on the canonical branch of Wnt signaling pathway, i.e., Wnt/β-catenin signaling. The Wnt/planar cell polarity (PCP) signaling pathway, as the most recently described branch of Wnt signaling, was much less investigated in oncology research. In this study, we thoroughly characterized the activity of the Wnt/PCP regulation pathway in low-grade glioma (LGG) patients. Subtyping based on the expression pattern of the Wnt/PCP regulation pathway revealed three (C1–C3) subgroups with significant survival differences. Each group displayed distinct genomic characteristics. For instance, C1 was enriched with capicua transcriptional repressor (CIC) truncating mutations and 1p19q codel. C2 was characterized with tumor protein p53 (TP53) and ATRX chromatin remodeler (ATRX) inactivating mutations but depletion of telomerase reverse transcriptase (TERT) promoter mutations. C3 showed elevated malignancy reflected from several oncogenic characteristics, such as tumor heterogeneity and cell stemness, and demonstrated the worst survival outcome. In addition, C3 showed elevated macrophage segregation via induction of cytokines that are able to enhance the permeability of the brain–blood barrier (BBB). Lastly, we developed a prognostic model based on the risk score system. Validation indicated that our model can independently predict the prognosis of LGG patients.