bluuebunny/crossref_metadata_2025 huggingface dataset:
Computational Saturation Mutagenesis of SARS-CoV-1 Spike Glycoprotein: Stability, Binding Affinity, and Comparison With SARS-CoV-2
Authors: Sobitan Adebiyi , Mahase Vidhyanand , Rhoades Raina , Williams Dejaun , Liu Dongxiao , Xie Yixin , Li Lin , Tang Qiyi , Teng Shaolei
Published: December 2021

Severe Acute respiratory syndrome coronavirus (SARS-CoV-1) attaches to the host cell surface to initiate the interaction between the receptor-binding domain (RBD) of its spike glycoprotein (S) and the human Angiotensin-converting enzyme (hACE2) receptor. SARS-CoV-1 mutates frequently because of its RNA genome, which challenges the antiviral development. Here, we per-formed computational saturation mutagenesis of the S protein of SARS-CoV-1 to identify the residues crucial for its functions. We used the structure-based energy calculations to analyze the effects of the missense mutations on the SARS-CoV-1 S stability and the binding affinity with hACE2. The sequence and structure alignment showed similarities between the S proteins of SARS-CoV-1 and SARS-CoV-2. Interestingly, we found that target mutations of S protein amino acids generate similar effects on their stabilities between SARS-CoV-1 and SARS-CoV-2. For example, G839W of SARS-CoV-1 corresponds to G857W of SARS-CoV-2, which decrease the stability of their S glycoproteins. The viral mutation analysis of the two different SARS-CoV-1 isolates showed that mutations, T487S and L472P, weakened the S-hACE2 binding of the 2003–2004 SARS-CoV-1 isolate. In addition, the mutations of L472P and F360S destabilized the 2003–2004 viral isolate. We further predicted that many mutations on N-linked glycosylation sites would increase the stability of the S glycoprotein. Our results can be of therapeutic importance in the design of antivirals or vaccines against SARS-CoV-1 and SARS-CoV-2.
Animal Models of Anxiety and Depression: Incorporating the Underlying Mechanisms of Sex Differences in Macroglia Biology
Authors: Wegener Amy J. , Neigh Gretchen N.
Published: December 2021

Animal models have been utilized to explore the mechanisms by which mood disorders develop. Ethologically based stress paradigms are used to induce behavioral responses consistent with those observed in humans suffering from anxiety and depression. While mood disorders are more often diagnosed in women, animal studies are more likely to be carried out in male rodents. However, understanding the mechanisms behind anxiety- and depressive-like behaviors in both sexes is necessary to increase the predictive and construct validity of the models and identify therapeutic targets. To understand sex differences following stress, we must consider how all cell types within the central nervous system are influenced by the neuroendocrine system. This review article discusses the effects of stress and sex steroids on the macroglia: astrocytes and oligodendrocytes. Glia are involved in shaping the synapse through the regulation of neurotransmitter levels and energy resources, making them essential contributors to neural dynamics following stress. As the role of glia in neuromodulation has become more apparent, studies exploring the mechanisms by which glia are altered by stress and steroids will provide insight into sex differences in animal models. These insights will facilitate the optimization of animal models of psychiatric disorders and development of future therapeutic targets.
Layer-Specific Vesicular Glutamate Transporter 1 Immunofluorescence Levels Delineate All Layers of the Human Hippocampus Including the Stratum lucidum
Authors: Woelfle Sarah , Boeckers Tobias M.
Published: December 2021

The hippocampal formation consists of the Ammon’s horn (cornu Ammonis with its regions CA1-4), dentate gyrus, subiculum, and the entorhinal cortex. The rough extension of the regions CA1-3 is typically defined based on the density and size of the pyramidal neurons without clear-cut boundaries. Here, we propose the vesicular glutamate transporter 1 (VGLUT1) as a molecular marker for the CA3 region. This is based on its strong labeling of the stratum lucidum (SL) in fluorescently stained human hippocampus sections. VGLUT1 puncta of the intense SL band co-localize with synaptoporin (SPO), a protein enriched in mossy fibers (MFs). Owing to its specific intensity profile throughout all hippocampal layers, VGLUT1 could be implemented as a pendant to Nissl-staining in fluorescent approaches with the additional demarcation of the SL. Furthermore, by high-resolution confocal microscopy, we detected VGLUT2 in the human hippocampus, thus reconciling two previous studies. Finally, by VGLUT1/SPO co-staining, we provide evidence for the existence of infrapyramidal MFs in the human hippocampus and we show that SPO expression is not restricted to MF synapses as demonstrated for rodent tissue.
Efficacy of Scalp Acupuncture in Patients With Post-stroke Hemiparesis: Meta-Analysis of Randomized Controlled Trials
Authors: Huang Yuan-Ju , Huang Chih-Shan , Leng Kuo-Feng , Sung Jia-Ying , Cheng Sheng-Wei
Published: December 2021

Objectives:To conduct a meta-analysis to assess the efficacy of scalp acupuncture (SA) in patients with stroke and consequent hemiparesis regardless of brain infarction or intracerebral hemorrhage.

Methods:A literature search of randomized controlled trials (RCTs) on SA for stroke was performed in five databases up to May 10, 2021. We investigated three types of outcome: motor function, sequelae of poststroke hemiparesis, and adverse effects. Methodological quality was assessed using the revised Cochrane risk of bias tool version 2.0.

Results:Of 1,063 papers, 30 RCTs involving Fugl–Meyer Assessment were selected, among which 10 and four RCTs were selected for evaluation of courses lasting of 1 and 3 months, respectively. The meta-analysis of 1- and 3-month courses revealed significant differences in the motor function of the SA plus Western standard treatment group vs. Western standard treatment only (medication plus rehabilitation;P< 0.001). A 3-month course tended to result in better outcomes than a 1-month course.

Conclusions:Our meta-analysis results reveal that SA improves motor function in patients with acute to chronic stroke, regardless of brain infarction or intracerebral hemorrhage. However, because of a lack of methodological quality, thoroughly planned clinical studies are still required.
Kinematic Changes in the Uninjured Limb After a Traumatic Brachial Plexus Injury
Authors: Souza Lidiane , Lustosa Luiggi , Silva Ana Elisa Lemos , Martins José Vicente , Pozzo Thierry , Vargas Claudia D.
Published: December 2021

Background: Traumatic brachial plexus injury (TBPI) typically causes sensory, motor and autonomic deficits of the affected upper limb. Recent studies have suggested that a unilateral TBPI can also affect the cortical representations associated to the uninjured limb.

Objective: To investigate the kinematic features of the uninjured upper limb in participants with TBPI.

Methods: Eleven participants with unilateral TBPI and twelve healthy controls matched in gender, age and anthropometric characteristics were recruited. Kinematic parameters collected from the index finger marker were measured while participants performed a free-endpoint whole-body reaching task and a cup-to-mouth task with the uninjured upper limb in a standing position.

Results: For the whole-body reaching task, lower time to peak velocity (p = 0.01), lower peak of velocity (p = 0.003), greater movement duration (p = 0.04) and shorter trajectory length (p = 0.01) were observed in the TBPI group compared to the control group. For the cup-to-mouth task, only a lower time to peak velocity was found for the TBPI group compared to the control group (p = 0.02). Interestingly, no differences between groups were observed for the finger endpoint height parameter in either of the tasks. Taken together, these results suggest that TBPI leads to a higher cost for motor planning when it comes to movements of the uninjured limb as compared to healthy participants. This cost is even higher in a task with a greater postural balance challenge.

Conclusion: This study expands the current knowledge on bilateral sensorimotor alterations after unilateral TBPI and should guide rehabilitation after a peripheral injury.
Assessing Causal Relationship Between Human Blood Metabolites and Five Neurodegenerative Diseases With GWAS Summary Statistics
Authors: Chen Haimiao , Qiao Jiahao , Wang Ting , Shao Zhonghe , Huang Shuiping , Zeng Ping
Published: December 2021

Background: Neurodegenerative diseases (NDDs) are the leading cause of disability worldwide while their metabolic pathogenesis is unclear. Genome-wide association studies (GWASs) offer an unprecedented opportunity to untangle the relationship between metabolites and NDDs.

Methods: By leveraging two-sample Mendelian randomization (MR) approaches and relying on GWASs summary statistics, we here explore the causal association between 486 metabolites and five NDDs including Alzheimer’s Disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson’s disease (PD), and multiple sclerosis (MS). We validated our MR results with extensive sensitive analyses including MR-PRESSO and MR-Egger regression. We also performed linkage disequilibrium score regression (LDSC) and colocalization analyses to distinguish causal metabolite-NDD associations from genetic correlation and LD confounding of shared causal genetic variants. Finally, a metabolic pathway analysis was further conducted to identify potential metabolite pathways.

Results: We detected 164 metabolites which were suggestively associated with the risk of NDDs. Particularly, 2-methoxyacetaminophen sulfate substantially affected ALS (OR = 0.971, 95%CIs: 0.961 ∼ 0.982, FDR = 1.04E-4) and FTD (OR = 0.924, 95%CIs: 0.885 ∼ 0.964, FDR = 0.048), and X-11529 (OR = 1.604, 95%CIs: 1.250 ∼ 2.059, FDR = 0.048) and X-13429 (OR = 2.284, 95%CIs: 1.457 ∼ 3.581, FDR = 0.048) significantly impacted FTD. These associations were further confirmed by the weighted median and maximum likelihood methods, with MR-PRESSO and the MR-Egger regression removing the possibility of pleiotropy. We also observed that ALS or FTD can alter the metabolite levels, including ALS and FTD on 2-methoxyacetaminophen sulfate. The LDSC and colocalization analyses showed that none of the identified associations could be driven by genetic correlation or confounding by LD with common causal loci. Multiple metabolic pathways were found to be involved in NDDs, such as “urea cycle” (P = 0.036), “arginine biosynthesis” (P = 0.004) on AD and “phenylalanine, tyrosine and tryptophan biosynthesis” (P = 0.046) on ALS.

Conclusion: our study reveals robust bidirectional causal associations between servaral metabolites and neurodegenerative diseases, and provides a novel insight into metabolic mechanism for pathogenesis and therapeutic strategies of these diseases.
Mapping the BCPNN Learning Rule to a Memristor Model
Authors: Wang Deyu , Xu Jiawei , Stathis Dimitrios , Zhang Lianhao , Li Feng , Lansner Anders , Hemani Ahmed , Yang Yu , Herman Pawel , Zou Zhuo
Published: December 2021

The Bayesian Confidence Propagation Neural Network (BCPNN) has been implemented in a way that allows mapping to neural and synaptic processes in the human cortexandhas been used extensively in detailed spiking models of cortical associative memory function and recently also for machine learning applications. In conventional digital implementations of BCPNN, the von Neumann bottleneck is a major challenge with synaptic storage and access to it as the dominant cost. The memristor is a non-volatile device ideal for artificial synapses that fuses computation and storage and thus fundamentally overcomes the von Neumann bottleneck. While the implementation of other neural networks like Spiking Neural Network (SNN) and even Convolutional Neural Network (CNN) on memristor has been studied, the implementation of BCPNN has not. In this paper, the BCPNN learning rule is mapped to a memristor model and implemented with a memristor-based architecture. The implementation of the BCPNN learning rule is a mixed-signal design with the main computation and storage happening in the analog domain. In particular, the nonlinear dopant drift phenomenon of the memristor is exploited to simulate the exponential decay of the synaptic state variables in the BCPNN learning rule. The consistency between the memristor-based solution and the BCPNN learning rule is simulated and verified in Matlab, with a correlation coefficient as high as 0.99. The analog circuit is designed and implemented in the SPICE simulation environment, demonstrating a good emulation effect for the BCPNN learning rule with a correlation coefficient as high as 0.98. This work focuses on demonstrating the feasibility of mapping the BCPNN learning rule to in-circuit computation in memristor. The feasibility of the memristor-based implementation is evaluated and validated in the paper, to pave the way for a more efficient BCPNN implementation, toward a real-time brain emulation engine.
Providing Task Instructions During Motor Training Enhances Performance and Modulates Attentional Brain Networks
Authors: Penalver-Andres Joaquin , Buetler Karin A. , Koenig Thomas , Müri René Martin , Marchal-Crespo Laura
Published: December 2021

Learning a new motor task is a complex cognitive and motor process. Especially early during motor learning, cognitive functions such as attentional engagement, are essential, e.g., to discover relevant visual stimuli. Drawing participant’s attention towards task-relevant stimuli—e.g., with task instructions using visual cues or explicit written information—is a common practice to support cognitive engagement during training and, hence, accelerate motor learning. However, there is little scientific evidence about how visually cued or written task instructions affect attentional brain networks during motor learning. In this experiment, we trained 36 healthy participants in a virtual motor task: surfing waves by steering a boat with a joystick. We measured the participants’ motor performance and observed attentional brain networks using alpha-band electroencephalographic (EEG) activity before and after training. Participants received one of the following task instructions during training: (1) No explicit task instructions and letting participants surf freely (implicit training; IMP); (2) Task instructions provided through explicit visual cues (explicit-implicit training; E-IMP); or (3) through explicit written commands (explicit training; E). We found that providing task instructions during training (E and E-IMP) resulted in less post-training motor variability—linked to enhanced performance—compared to training without instructions (IMP). After training, participants trained with visual cues (E-IMP) enhanced the alpha-band strength over parieto-occipital and frontal brain areas at wave onset. In contrast, participants who trained with explicit commands (E) showed decreased fronto-temporal alpha activity. Thus, providing task instructions in written (E) or using visual cues (E-IMP) leads to similar motor performance improvements by enhancing activation on different attentional networks. While training with visual cues (E-IMP) may be associated with visuo-attentional processes, verbal-analytical processes may be more prominent when written explicit commands are provided (E). Together, we suggest that training parameters such as task instructions, modulate the attentional networks observed during motor practice and may support participant’s cognitive engagement, compared to training without instructions.
A Comparative Study of Diffusion Fiber Reconstruction Models for Pyramidal Tract Branches
Authors: Suo Xinjun , Guo Lining , Fu Dianxun , Ding Hao , Li Yihong , Qin Wen
Published: December 2021

Currently, comparative studies evaluating the quantification accuracy of pyramidal tracts (PT) and PT branches that were tracked based on four mainstream diffusion models are deficient. The present study aims to evaluate four mainstream models using the high-quality Human Connectome Project (HCP) dataset. Diffusion tensor imaging (DTI), diffusion spectral imaging (DSI), generalized Q-space sampling imaging (GQI), and Q-ball imaging (QBI) were used to construct the PT and PT branches in 50 healthy volunteers from the HCP. False and true PT fibers were identified based on anatomic information. One-way repeated measure analysis of variance and post hoc paired-sample t-test were performed to identify the best PT and PT branch quantification model. The number, percentage, and density of true fibers of PT obtained based on GQI and QBI were significantly larger than those based on DTI and DSI (all p < 0.0005, Bonferroni corrected), whereas false fibers yielded the opposite results (all p < 0.0005, Bonferroni corrected). More trunk branches (PTtrunk) were present in the four diffusion models compared with the upper limb (PTUlimb), lower limb (PTLlimb), and cranial (PTcranial) branches. In addition, significantly more true fibers were obtained in PTtrunk, PTUlimb, and PTLlimb based on the GQI and QBI compared with DTI and DSI (all p < 0.0005, Bonferroni corrected). Finally, GQI-based group probabilistic maps showed that the four PT branches exhibited relatively unique spatial distributions. Therefore, the GQI and QBI represent better diffusion models for the PT and PT branches. The group probabilistic maps of PT branches have been shared with the public to facilitate more precise studies on the plasticity of and the damage to the motor pathway.
Association Between Dietary Patterns and Plasma Lipid Biomarker and Female Breast Cancer Risk: Comparison of Latent Class Analysis (LCA) and Factor Analysis (FA)
Authors: Cao Shang , Liu Linchen , Zhu Qianrang , Zhu Zheng , Zhou Jinyi , Wei Pingmin , Wu Ming
Published: December 2021

Background: Diet research focuses on the characteristics of “dietary patterns” regardless of the statistical methods used to derive them. However, the solutions to these methods are both conceptually and statistically different.

Methods: We compared factor analysis (FA) and latent class analysis (LCA) methods to identify the dietary patterns of participants in the Chinese Wuxi Exposure and Breast Cancer Study, a population-based case-control study that included 818 patients and 935 healthy controls. We examined the association between dietary patterns and plasma lipid markers and the breast cancer risk.

Results: Factor analysis grouped correlated food items into five factors, while LCA classified the subjects into four mutually exclusive classes. For FA, we found that the Prudent-factor was associated with a lower risk of breast cancer [4th vs. 1st quartile: odds ratio (OR) for 0.70, 95% CI = 0.52, 0.95], whereas the Picky-factor was associated with a higher risk (4th vs. 1st quartile: OR for 1.35, 95% CI = 1.00, 1.81). For LCA, using the Prudent-class as the reference, the Picky-class has a positive association with the risk of breast cancer (OR for 1.42, 95% CI = 1.06, 1.90). The multivariate-adjusted model containing all of the factors was better than that containing all of the classes in predicting HDL cholesterol (p = 0.04), triacylglycerols (p = 0.03), blood glucose (p = 0.04), apolipoprotein A1 (p = 0.02), and high-sensitivity C-reactive protein (p = 0.02), but was weaker than that in predicting the breast cancer risk (p = 0.03).

Conclusion: Factor analysis is useful for understanding which foods are consumed in combination and for studying the associations with biomarkers, while LCA is useful for classifying individuals into mutually exclusive subgroups and compares the disease risk between the groups.
Reducing Disease Activity of Inflammatory Bowel Disease by Consumption of Plant-Based Foods and Nutrients
Authors: Antoniussen Christian S. , Rasmussen Henrik H. , Holst Mette , Lauridsen Charlotte
Published: December 2021

Inflammatory bowel disease is a chronic and recurring inflammatory condition of the gastrointestinal tract encompassing ulcerative colitis and Crohn's disease. Although the pathogenesis of inflammatory bowel disease remains to be fully elucidated, environmental factors such as diet are believed to play a pivotal role in the onset and management of inflammatory bowel disease. Diet is thought to play an essential role in intestinal inflammation due to its regulatory effects on the microbiota, gut immune system, and epithelial barrier function. Although the evidence remains insufficient to draw firm conclusions on the role of specific dietary components in gastrointestinal diseases, studies have suggested that a Western diet with high intakes of total fats, omega-6 fatty acids, and meat have been associated with intestinal inflammation and relapse of inflammatory bowel disease. In contrast to a Western diet, plant-based diets often result in a reduced intake of total fats and meats and an increased intake of plant fibers which may contribute to reduced intestinal inflammation. This review critically examines the influence of plant-based dietary components on the clinical disease course of inflammatory bowel disease. Furthermore, this review discusses the benefits and possible limitations of plant-derived dietary components in the treatment of inflammatory bowel disease while addressing the principal type of disease and the anatomic site of inflammation within the gastrointestinal tract. Finally, this review points out important directions for future research on the role of diet in inflammatory bowel disease. A better understanding of the role of diet and intestinal inflammation may pave the way for novel dietary interventions and specific foods- or food supplements, which can support the treatment of inflammatory bowel disease.
Efficacy and Safety of Brucea javanica Oil Emulsion Injection in the Treatment of Gastric Cancer: A Systematic Review and Meta-Analysis
Authors: Wang Xinmiao , Wang Heping , Cao Luchang , Wu Jingyuan , Lu Taicheng , Li Shixin , Li Jie
Published: December 2021

Background: Gastric cancer (GC) is one of the most common digestive tract cancers and ranks fifth in the incidence of malignant tumors worldwide. Brucea javanica oil emulsion injection (BJOEI), a Chinese patent medicine extracted from Brucea javanica (Yadanzi in Chinese Pinyin), is widely used as an adjuvant treatment for GC in China. This systematic review and meta-analysis aimed to evaluate the available data on the efficacy and safety of BJOEI in the treatment of GC and assess the quality of the synthesized evidence.

Methods: A comprehensive search was performed on PubMed, EMBASE, CENTRAL, Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Wanfang database and Chinese Scientific Journals Database (VIP database), and other potential resources, such as the Chinese Clinical Trial Registry (ChiCTR) and ClinicalTrials.gov from their inception to July 31, 2021. Randomized controlled trials (RCTs) comparing the therapeutic effects of BJOEI combined with conventional therapy to those of conventional therapy alone were included. We used RevMan 5.3 for data analysis and quality evaluation of the included studies and assessed the evidence quality based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria.

Results: Eighteen RCTs involving 1,210 patients were included, and the meta-analysis results demonstrated that compared with the control group (conventional therapy), the experimental group (BJOEI combined with conventional therapy) showed a significantly improved overall response rate (ORR) (risk ratio [RR] = 1.52, 95% CI: 1.36–1.69, P < 0.00001), clinical benefit rate (CBR) (RR = 1.17, 95% CI: 1.11–1.23, P < 0.00001), performance status (RR = 1.72, 95% CI: 1.46–2.01, P < 0.00001), and reduced incidence of the following adverse drug reactions (ADRs): neutropenia, leukopenia, nausea and vomiting, diarrhea, liver damage, hand-foot syndrome, and peripheral sensory nerve toxicity. Subgroup analysis showed that the BJOEI intervention could significantly improve the ORR and CBR in patients with GC when combined with FOLFOX4, XELOX, and other chemotherapeutics.

Conclusion: The evidence presented in this study supports the fact that BJOEI combined with conventional chemotherapy provides a statistically significant and clinically important effect in the improvement of ORR, CBR, performance status, and ADR reduction in patients with GC. To further support this conclusion, more rigorously designed, large-scale, and multicenter RCTs are needed in the future.
Lobectomy Versus Sublobectomy in Stage IIIA/N2 Non-Small Cell Lung Cancer: A Population-Based Study
Authors: Wang Suyu , Zhang Zhiyuan , Gu Yang , Lv Xin , Shi Xuan , Liu Meiyun
Published: December 2021

Background

The role lobectomy plays in stage IIIA/N2 non-small cell lung cancer (NSCLC) is controversial for a long time. What’s more, no previous study concentrates on whether sublobectomy can improve survival outcome for these patients, so we performed this population-based study to investigate whether stage IIIA/N2 NSCLC can benefit from these two surgery types and compare survival outcomes after lobectomy and sublobectomy.

Methods

A total of 21,638 patients diagnosed with stage IIIA/N2 NSCLC between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database matched our selection criteria. The study cohort included patients who received no surgery (n = 15,951), sublobectomy (n = 628) and lobectomy (n = 5,059). Kaplan–Meier method, Cox regression analyses, and inverse probability of treatment weighting (IPTW)-adjusted Cox regression were used to illustrate the influence of sublobectomy and lobectomy on overall survival (OS) rates in the study cohort and compare these two surgery types.

Results

Multivariable Cox regression analysis showed sublobectomy [HR: 0.584 (95%CI: 0.531–0.644), P-value <0.001; IPTW-adjusted HR: 0.619 (95%CI: 0.605–0.633), P-value <0.001] and lobectomy [HR: 0.439 (95%CI: 0.420–0.459), P-value <0.001; IPTW-adjusted HR: 0.441 (95%CI: 0.431–0.451), P-value <0.001] were both related to better OS rates compared with no surgery, and lobectomy exhibited better survival than sublobectomy [HR: 0.751 (95%CI: 0.680–0.830), P-value <0.001; IPTW-adjusted HR: 0.713 (95%CI: 0.696–0.731), P-value <0.001]. Moreover, the results in subgroup analyses based on age, tumor size and radiotherapy and chemotherapy strategy in all study cohort were consistent.

Conclusion

Stage IIIA/N2 NSCLC patients could benefit from sublobectomy or lobectomy, and lobectomy provided better OS rates than sublobectomy.
Predictive and Prognostic Effects of Primary Tumor Size on Colorectal Cancer Survival
Authors: Alese Olatunji B. , Zhou Wei , Jiang Renjian , Zakka Katerina , Huang Zhonglu , Okoli Chimuanya , Shaib Walid L. , Akce Mehmet , Diab Maria , Wu Christina , El-Rayes Bassel F.
Published: December 2021

Background

Pathologic staging is crucial in colorectal cancer (CRC). Unlike the majority of solid tumors, the current staging model does not use tumor size as a criterion. We evaluated the predictive and prognostic impact of primary tumor size on all stages of CRC.

Methods

Using the National Cancer Database (NCDB), we conducted an analysis of CRC patients diagnosed between 2010 and 2015 who underwent resection of their primary cancer. Univariate and multivariate analyses were used to identify predictive and prognostic factors, Kaplan-Meier analysis and Cox proportional hazards models for association between tumor size and survival.

Results

About 61,000 patients met the inclusion criteria. Median age was 63 years and majority of the tumors were colon primary (82.7%). AJCC stage distribution was: I - 20.1%; II - 32.1%; III - 34.7% and IV - 13.1%. The prognostic impact of tumor size was strongly associated with survival in stage III disease. Compared to patients with tumors <2cm; those with 2-5cm (HR 1.33; 1.19-1.49; p<0.001), 5-10cm (HR 1.51 (1.34-1.70; p<0.001) and >10cm (HR 1.95 (1.65-2.31; p<0.001) had worse survival independent of other variables. Stage II treated without adjuvant chemotherapy had comparable survival outcomes (HR 1.09; 0.97-1.523; p=0.148) with stage III patients who did, while Stage II patients who received adjuvant chemotherapy did much better than both groups (HR 0.76; 0.67-0.86; p<0.001). Stage III patients who did not receive adjuvant chemotherapy had the worst outcomes among the non-metastatic disease subgroups (HR 2.66; 2.48-2.86; p<0.001). Larger tumors were associated with advanced stage, MSI high, non-rectal primary and positive resection margins.

Conclusions

Further studies are needed to clarify the role of tumor size in prognostic staging models, and how to incorporate it into therapy decisions.
Identification of Whole-Serum Glycobiomarkers for Colorectal Carcinoma Using Reverse-Phase Lectin Microarray
Authors: Bertok Tomas , Bertokova Aniko , Jane Eduard , Hires Michal , Aguedo Juvissan , Potocarova Maria , Lukac Ludovit , Vikartovska Alica , Kasak Peter , Borsig Lubor , Tkac Jan
Published: December 2021

Colorectal cancer (CRC) is one of the most common types of cancer among men and women worldwide. Efforts are currently underway to find novel and more cancer-specific biomarkers that could be detected in a non-invasive way. The analysis of aberrant glycosylation of serum glycoproteins is a way to discover novel diagnostic and prognostic CRC biomarkers. The present study investigated a whole-serum glycome with a panel of 16 different lectins in search for age-independent and CRC-specific glycomarkers using receiver operating characteristic (ROC) curve analyses and glycan heat matrices. Glycosylation changes present in the whole serum were identified, which could lead to the discovery of novel biomarkers for CRC diagnostics. In particular, the change in the bisecting glycans (recognized by Phaseolus vulgaris erythroagglutinin) had the highest discrimination potential for CRC diagnostics in combination with human L selectin providing area under the ROC curve (AUC) of 0.989 (95% CI 0.950–1.000), specificity of 1.000, sensitivity of 0.900, and accuracy of 0.960. We also implemented novel tools for identification of lectins with strong discrimination power.
Immune Checkpoint Inhibitor Induced Pericarditis and Encephalitis in a Patient Treated With Ipilimumab and Nivolumab for Metastatic Melanoma: A Case Report and Review of the Literature
Authors: Braden Jorja , Lee Jenny H.
Published: December 2021

Immune checkpoint inhibitors (ICIs) have dramatically improved outcomes in melanoma. Common ICI toxicities have become familiar to clinicians; however, rare delayed toxicities remain challenging given the paucity of data with such presentations. We present the unique case of a 61-year-old with metastatic melanoma with two rare, delayed ICI-induced toxicities. After resection of a large symptomatic parietal metastases, this patient received two doses of combination ipilimumab and nivolumab. Five weeks following his second dose, he developed ICI-induced pericarditis with associated pericardial effusion and early signs of tamponade. Corticosteroids were not administered due to a concurrent cerebral abscess. Administration of colchicine, ibuprofen, judicious monitoring, and cessation of immunotherapy led to the complete resolution of the effusion over several weeks. Seven months following his last dose of immunotherapy, the patient developed ICI-associated grade four autoimmune encephalitis, presenting as status epilepticus. High-dose steroid initiation led to rapid clinical improvement. The patient remains in near-complete response on imaging with no recurrence of pericardial effusion and partial resolution of neurological symptoms. ICI-induced pericardial disease and encephalitis carry substantial mortality rates and prompt diagnosis and management is critical. Clinicians must therefore remain vigilant for these rare toxicities regardless of duration of drug exposure or time since cessation of therapy.
miR-616-5p Promotes Invasion and Migration of Bladder Cancer via Downregulating NR2C2 Expression
Authors: Ren Wenbiao , Hu Jiao , Li Huihuang , Chen Jinbo , Ding Jian , Zu Xiongbing , Fan Benyi
Published: December 2021

Background

MicroRNAs, small non-coding RNA molecules with about 22 nucleotides in length, play a significant role in the development of bladder cancer. Previous studies found that miR-616-5p could promote the progress of cancers. However, its role in bladder cancer remains unclear. In the study, we aimed to demonstrate how miR-616-5p impacts the invasion and migration of bladder cancer and its potential downstream targets.

Methods

Firstly, qRT-PCR was used to detect the expression of miR-616-5p in normal bladder uroepithelial cell lines and bladder cancer cell lines. Then, chamber–transwell invasion and wound healing migration assays were used to detect the roles of miR-616-5p and NR2C2 in invasion and migration. Subsequently, Western blot was used to evaluate the regulation effects of miR-616-5p and NR2C2. Finally, luciferase assays were performed to manifest the mechanism of miR-616-5p and NR2C2 regulation.

Results

We found that miR-616-5p was upregulated in bladder cancer, and it could promote the invasion and migration of bladder cancer in vitro. Moreover, we demonstrated that NR2C2 was a downstream target of miR-616-5p. miR-616-5p could inhibit the expression of NR2C2 by binding to the 3′UTR of NR2C2 mRNA. Importantly, patients with a high expression of NR2C2 showed better prognoses in bladder cancer.

Conclusions

This study identifies that miR-616-5p can promote bladder cancer progression via altering the expression of NR2C2. Therefore, identifying miR-616-5p expression levels might be a useful strategy for developing potential therapeutic targets in bladder cancer.
EUS-FNA Biopsies to Guide Precision Medicine in Pancreatic Cancer: Results of a Pilot Study to Identify KRAS Wild-Type Tumours for Targeted Therapy
Authors: Lundy Joanne , Harris Marion , Zalcberg John , Zimet Allan , Goldstein David , Gebski Val , Borsaru Adina , Desmond Christopher , Swan Michael , Jenkins Brendan J. , Croagh Daniel
Published: December 2021

Background

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death and lacks effective treatment options. Diagnostic endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsies represent an appealing source of material for molecular analysis to inform targeted therapy, as they are often the only available tissue for patients presenting with PDAC irrespective of disease stage. However, EUS-FNA biopsies are typically not used to screen for precision medicine studies due to concerns about low tissue yield and quality. Epidermal growth factor receptor (EGFR) inhibition has shown promise in clinical trials of unselected patients with advanced pancreatic cancer, but has not been prospectively tested in KRAS wild-type patients. Here, we examine the clinical utility of EUS-FNA biopsies for molecular screening of KRAS wild-type PDAC patients for targeted anti-EGFR therapy to assess the feasibility of this approach.

Patients and Methods

Fresh frozen EUS-FNA or surgical biopsies from PDAC patient tumours were used to screen for KRAS mutations. Eligible patients with recurrent, locally advanced, or metastatic KRAS wild-type status who had received at least one prior line of chemotherapy were enrolled in a pilot study (ACTRN12617000540314) and treated with panitumumab at 6mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was 4-month progression-free survival (PFS).

Results

275 patient biopsies were screened for KRAS mutations, which were detected in 88.3% of patient samples. 8 eligible KRAS wild-type patients were enrolled onto the interventional study between November 2017 and December 2020 and treated with panitumumab. 4-month PFS was 14.3% with no objective tumour responses observed. The only grade 3/4 treatment related toxicity observed was hypomagnesaemia.

Conclusions

This study demonstrates proof-of-principle feasibility to molecularly screen patients with pancreatic cancer for targeted therapies, and confirms diagnostic EUS-FNA biopsies as a reliable source of tumour material for molecular analysis. Single agent panitumumab was safe and tolerable but led to no objective tumour responses in this population.
The Incidence Rate and Risk Factors of Malignancy in Elderly-Onset Inflammatory Bowel Disease: A Chinese Cohort Study From 1998 to 2020
Authors: Wang Zheng , Zhang Huimin , Yang Hong , Zhang Mengmeng , Qian Jiaming
Published: December 2021

Background

Patients suffering from inflammatory bowel disease (IBD) have an increased risk of cancer. However, the risk of malignancy in patients with elderly-onset IBD (≥60 years) remains controversial. Hence, we aimed to identify and compare the dissimilarities in morbidity and related risk factors between patients with elderly-onset and adult-onset (18–59 years) IBD in a Chinese cohort.

Methods

Patients with confirmed IBD, diagnosed at age ≥18 years, between January 1998 and December 2020 at the Peking Union Medical College Hospital were enrolled. The yearly incidence rates (IRs) for cancer were calculated, and the characteristics were analyzed in these patients.

Results

A total of 1,480 patients suffering from adult-onset IBD and 129 patients suffering from elderly-onset IBD with a median follow-up period of 4.9 years and 4.8 years, respectively, were included. Patients in the elderly-onset IBD group demonstrated an increased overall incidence of cancer than that demonstrated by patients in the adult-onset group (IR 26.9 versus 9.51, respectively, per 1,000 person-years; relative risk [RR], 2.83). Colorectal cancer was the most common malignancy in the two groups, and patients suffering from elderly-onset IBD demonstrated a higher incidence of the malignancy (IR, 7.07 versus 3.34, respectively, per 1,000 person-years; RR, 2.12). Among the extraintestinal cancers, hematological malignancies and urinary tract cancers (including renal and urinary bladder carcinoma) were common in the elderly-onset group (IR, 4.24 and 4.24 per 1,000 person-years, respectively), whereas thyroid cancer was more common in the adult-onset group (IR, 1.36 per 1,000 person-years). Analysis of clinical characteristics revealed that patients with elderly-onset IBD who developed cancer were more likely to have diabetes and urinary lithiasis (p = 0.041 and 0.035, respectively). In addition, patients in the elderly-onset group had a shorter course from IBD to cancer, less exposure to immunosuppressants, less extraintestinal manifestations, and higher cancer-related mortality. Cox proportional risk regression analysis in the elderly-onset IBD group revealed that diabetes was an independent risk factor for the progression to cancer (hazard ratio [HR], 12.53 [2.379–65.994], P = 0.003).

Conclusion

The risk of malignancy in patients suffering from elderly-onset IBD increased significantly as compared with those with adult-onset disease. Therefore, cancer monitoring should be initiated earlier for patients in the elderly-onset group.
Giant Ovarian Cysts Treated by Single-Port Laparoscopic Surgery: A Case Series
Authors: Jiang Lili , Zhao Xinyu , Han Yue , Liu Kuiran , Meng Xinyue
Published: December 2021

Background

Ovarian cysts are very common diseases of the female reproductive system. Giant ovarian cysts refer to the tumors with diameters greater than 10 cm. In recent years, due to the development of clinical diagnosis, imaging modalities, and the improvement of patients’ cognition of the diseases, the occurrence of giant ovarian cysts has become rare. The purpose of this study was to show a new operation method of single-port laparoscopy to treat giant ovarian cysts.

Methods

We report a case series of five patients with giant ovarian cysts who underwent single-port laparoscopic surgery in the gynecology department of the Shengjing Hospital of China Medical University between June 2020 and March 2021. The inclusion criteria were ovarian cysts at least 20 cm in diameter, and cases when the tumor might be malignant were excluded.

Results

The patients’ mean age was 26.2years. The most common clinical presentation was progressive abdominal distension. Median size of the cysts at imaging was 39.2 cm (range 21–63 cm). All patients underwent single-port laparoscopic surgery, and none of them converted to laparotomy. On final pathological reports, two cysts were serous cystadenomas, and three were mucinous cystadenomas. All patients recovered well and were discharged on time.

Conclusion

Giant ovarian cysts can be treated by single-port laparoscopic surgery. In addition to the well-known advantages of laparoscopic surgery (e.g., small pelvic interference, fast postoperative recovery), it can also play the role of perfect cosmetic results, which has more advantages for young women.
The Association of MEG3 Gene rs7158663 Polymorphism With Cancer Susceptibility
Authors: Gao Xueren , Li Xianyang , Zhang Shulong , Wang Xiaoting
Published: December 2021

Although the association of MEG3 gene rs7158663 polymorphism with cancer susceptibility has been investigated, the findings are inconsistent. The aim of this study was to analyze the association between the rs7158663 polymorphism and cancer susceptibility through a case-control study and meta-analysis. In a case-control study with 430 colorectal cancer (CRC) cases and 445 healthy controls, the rs7158663 polymorphism was genotyped by direct sequencing. STATA software was used to calculate the pooled odds ratio and 95% confidence interval in a meta-analysis including 4,649 cancer cases and 5,590 controls. Both the case-control study and meta-analysis showed that the rs7158663 polymorphism was associated with increased susceptibility to CRC. Individuals carrying the AA or GA genotype were more likely to develop CRC than those carrying the rs7158663 GG genotype. Interestingly, MEG3 expression was significantly lower in colorectal tissues of the AA or GA genotype compared to those of the rs7158663 GG genotype. In addition, the meta-analysis suggested that the rs7158663 polymorphism was also associated with increased susceptibility to breast cancer and gastric cancer. Bioinformatics analysis showed that the rs7158663 A allele contributed to the binding of hsa-miR-4307 and hsa-miR-1265 to MEG3. In conclusion, the current findings suggest that the MEG3 gene rs7158663 polymorphism may serve as a genetic marker for predicting the risk of cancers, such as breast cancer, gastric cancer and CRC. However, the sample size of the current study is still insufficient, especially in the subgroup analysis. Therefore large and well-designed studies are needed to validate our findings.
A Combined Histone Deacetylases Targeting Strategy to Overcome Venetoclax Plus Azacitidine Regimen Resistance in Acute Myeloid Leukaemia: Three Case Reports
Authors: Wang Bin-Ru , Wan Chao-Ling , Liu Song-Bai , Qiu Qiao-Cheng , Wu Tian-Mei , Wang Jun , Li Yan-Yan , Ge Shuai-Shuai , Qiu Yan , Shen Xiang-Dong , Xue Sheng-Li , Li Zheng
Published: December 2021

The management of patients with relapsed or refractory (R/R) acute myeloid leukaemia (AML) remains a challenge with few reliably effective treatments. Chidamide, a new selective HDAC inhibitor, has demonstrated some effectiveness in AML patients. Herein, we reported three patients with R/R AML who were unresponsive to venetoclax plus azacitidine (VA) but were successfully treated with VA when chidamide was added to the regimen. MCL1 is one of the anti-apoptotic proteins. Chidamide targets the MCL1 protein, which may permit venetoclax resistance when upregulated. We determined MCL1 protein expression in different AML cell lines, and chidamide could downregulate MCL1 expression in venetoclax resistance AML cells. In general, our experience showed that the chidamide/VA combination could improve the condition of R/R AML patients who are resistant to VA. Formally evaluating this regimen in R/R AML patients may be meaningful.
The Research Progress of PD-1/PD-L1 Inhibitors Enhancing Radiotherapy Efficacy
Authors: Wen Lu , Tong Fan , Zhang Ruiguang , Chen Lingjuan , Huang Yu , Dong Xiaorong
Published: December 2021

Approximately 60%–70% of patients with malignant tumours require radiotherapy. The clinical application of immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1, has revolutionized cancer treatment and greatly improved the outcome of a variety of cancers by boosting host immunity.However, radiotherapy is a double-edged sword for PD-1/PD-L immunotherapy. Research on how to improve radiotherapy efficacy using PD-1/PD-L1 inhibitor is gaining momentum. Various studies have reported the survival benefits of the combined application of radiotherapy and PD-1/PD-L1 inhibitor. To fully exerts the immune activation effect of radiotherapy, while avoiding the immunosuppressive effect of radiotherapy as much as possible, the dose selection, segmentation mode, treatment timing and the number of treatment sites of radiotherapy play a role. Therefore, we aim to review the effect of radiotherapy combined with anti-PD-1/PD-L1 on the immune system and its optimization.
Characterization of Uterine Cervix Cancers in Women from Appalachian Kentucky
Authors: Kunos Charles A. , Fabian Denise , Kudrimoti Mahesh , Miller Rachel W. , Ueland Frederick R. , Randall Marcus E.
Published: December 2021

Uterine cervix cancer (UCCx) is clinically and socioeconomically diverse among women in the United States (US), which obscures the discovery of effective radiochemotherapy approaches for this disease. UCCx afflicts 7.5 per 100,000 American women nationally but 11.7 per 100,000 women in Appalachian Kentucky (AppKY), when age-adjusted to the 2000 US standard population. Epidemiological chart review was performed on 212 women with UCCx treated at the University of Kentucky (UKY) between January 2001 and July 2021. Demographics, tumor characteristics, and relative radiochemotherapy dose and schedule intensity were compared among AppKY and non-AppKY cohorts as well as Surveillance, Epidemiology, and End Results (SEER) data. One hundred thirty-eight (65%) of 212 women seeking radiochemotherapy treatment for UCCx resided in AppKY. Most (80%) sought external-beam radiochemotherapy close to their AppKY residence. Brachytherapy was then most frequently (96%) conducted at UKY. Cancer stage at diagnosis was significantly more advanced in AppKY residents. Women residing in AppKY had a median 10-week radiochemotherapy course, longer than an 8-week guideline. Estimated survival in women residing in AppKY was 8% lower than US national averages. In summary, this study identified an increased percentage of advanced-stage UCCx cancer at diagnosis arising in AppKY residents, with a confounding population-specific delay in radiochemotherapy schedule intensity lowering survival.