bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep Brain Stimulation: Emerging Tools for Simulation, Data Analysis, and Visualization
Authors: Wårdell Karin , Nordin Teresa , Vogel Dorian , Zsigmond Peter , Westin Carl-Fredrik , Hariz Marwan , Hemm Simone
Published: April 2022

Deep brain stimulation (DBS) is a well-established neurosurgical procedure for movement disorders that is also being explored for treatment-resistant psychiatric conditions. This review highlights important consideration for DBS simulation and data analysis. The literature on DBS has expanded considerably in recent years, and this article aims to identify important trends in the field. During DBS planning, surgery, and follow up sessions, several large data sets are created for each patient, and it becomes clear that any group analysis of such data is a big data analysis problem and has to be handled with care. The aim of this review is to provide an update and overview from a neuroengineering perspective of the current DBS techniques, technical aids, and emerging tools with the focus on patient-specific electric field (EF) simulations, group analysis, and visualization in the DBS domain. Examples are given from the state-of-the-art literature including our own research. This work reviews different analysis methods for EF simulations, tractography, deep brain anatomical templates, and group analysis. Our analysis highlights that group analysis in DBS is a complex multi-level problem and selected parameters will highly influence the result. DBS analysis can only provide clinically relevant information if the EF simulations, tractography results, and derived brain atlases are based on as much patient-specific data as possible. A trend in DBS research is creation of more advanced and intuitive visualization of the complex analysis results suitable for the clinical environment.
Cerebral Blood Flow Hemispheric Asymmetry in Comatose Adults Receiving Extracorporeal Membrane Oxygenation
Authors: Johnson Thomas W. , Dar Irfaan A. , Donohue Kelly L. , Xu Yama Y. , Santiago Esmeralda , Selioutski Olga , Marinescu Mark A. , Maddox Ross K. , Wu Tong Tong , Schifitto Giovanni , Gosev Igor , Choe Regine , Khan Imad R.
Published: April 2022

Peripheral veno-arterial extracorporeal membrane oxygenation (ECMO) artificially oxygenates and circulates blood retrograde from the femoral artery, potentially exposing the brain to asymmetric perfusion. Though ECMO patients frequently experience brain injury, neurologic exams and imaging are difficult to obtain. Diffuse correlation spectroscopy (DCS) non-invasively measures relative cerebral blood flow (rBF) at the bedside using an optical probe on each side of the forehead. In this study we observed interhemispheric rBF differences in response to mean arterial pressure (MAP) changes in adult ECMO recipients. We recruited 13 subjects aged 21–78 years (7 with cardiac arrest, 4 with acute heart failure, and 2 with acute respiratory distress syndrome). They were dichotomizedviaGlasgow Coma Scale Motor score (GCS-M) into comatose (GCS-M ≤ 4;n= 4) and non-comatose (GCS-M > 4;n= 9) groups. Comatose patients had greater interhemispheric rBF asymmetry (ASYMrBF) vs. non-comatose patients over a range of MAP values (29 vs. 11%,p= 0.009). ASYMrBFin comatose patients resolved near a MAP range of 70–80 mmHg, while rBF remained symmetric through a wider MAP range in non-comatose patients. Correlations between post-oxygenator pCO2or pH vs. ASYMrBFwere significantly different between comatose and non-comatose groups. Our findings indicate that comatose patients are more likely to have asymmetric cerebral perfusion.
Dual Passive Reactive Brain-Computer Interface: A Novel Approach to Human-Machine Symbiosis
Authors: Dehais Frédéric , Ladouce Simon , Darmet Ludovic , Nong Tran-Vu , Ferraro Giuseppe , Torre Tresols Juan , Velut Sébastien , Labedan Patrice
Published: April 2022

The present study proposes a novel concept of neuroadaptive technology, namely a dual passive-reactive Brain-Computer Interface (BCI), that enables bi-directional interaction between humans and machines. We have implemented such a system in a realistic flight simulator using the NextMind classification algorithms and framework to decode pilots' intention (reactive BCI) and to infer their level of attention (passive BCI). Twelve pilots used the reactive BCI to perform checklists along with an anti-collision radar monitoring task that was supervised by the passive BCI. The latter simulated an automatic avoidance maneuver when it detected that pilots missed an incoming collision. The reactive BCI reached 100% classification accuracy with a mean reaction time of 1.6 s when exclusively performing the checklist task. Accuracy was up to 98.5% with a mean reaction time of 2.5 s when pilots also had to fly the aircraft and monitor the anti-collision radar. The passive BCI achieved aF1−score of 0.94. This first demonstration shows the potential of a dual BCI to improve human-machine teaming which could be applied to a variety of applications.
The AHA Recommendations for a Healthy Diet and Ultra-Processed Foods: Building a New Diet Quality Index
Authors: Cacau Leandro Teixeira , Marcadenti Aline , Bersch-Ferreira Angela Cristine , Weber Bernardete , Almeida Jussara Carnevale de , Rodrigues Cíntia Corte Real , Lotufo Paulo Andrade , Bensenor Isabela Martins , Marchioni Dirce Maria
Published: April 2022

The American Heart Association (AHA) has developed the concept of “ideal cardiovascular health” (ICH), a seven-component score, which includes health dietary metrics. Higher ultra-processed foods intake is related with several cardiometabolic and cardiovascular diseases. We propose to develop and validate the Cardiovascular Health Diet Index (CHDI), a diet quality index that combines the AHA's recommendations of a healthy diet for cardiovascular health and ultra-processed foods. We used dietary data obtained through a 114-item FFQ from 14,779 participants of the Brazilian Longitudinal Study of Adults Health (ELSA-Brasil). The CHDI had 11 components and a total score ranging from 0 to 110 points. Validation and reliability analyses were performed, including principal component analyses, association with selected nutrients, means differences between groups (for example, smokers vs. non-smokers), Cronbach's alpha, and linear regression analyses between CHDI and overall dietary quality. The mean CHDI was 57.1 points (95% CI 47.9:66.0). The CHDI had four dimensions; in addition, it was associated with nutrients related to cardiovascular health, and the points were significantly (p < 0.001) lower in smokers (52.1) than in non-smokers (57.8). Cronbach's alpha value was 0.50. After age and sex adjustment, the CHDI score remained associated with a higher overall dietary quality (β 0.87, 95%CI 0.84:0.89, p < 0.001). The CHDI proved to be valid and reliable for use, in addition to being associated with higher overall dietary quality. The use of CHDI is expected to assess the population's compliance with dietary recommendations for promoting cardiovascular health and preventing cardiovascular disease.
Long Term Weight Loss Diets and Obesity Indices: Results of a Network Meta-Analysis
Authors: Jabbour Jana , Rihawi Yasmin , Khamis Assem M. , Ghamlouche Layal , Tabban Bayan , Safadi Gloria , Hammad Nour , Hadla Ruba , Zeidan Marwa , Andari Dana , Azar Riwa Nour , Nasser Nadine , Chakhtoura Marlene
Published: April 2022

Background

Scientists have been investigating efficient interventions to prevent and manage obesity. This network meta-analysis (NMA) compared the effect of different diets [moderate macronutrients (MMs), low fat/high carbohydrate (LFHC), high fat/low carbohydrate (HFLC), and usual diet (UD)] on weight, body mass index (BMI), and waist circumference (WC) changes at ≥12 months.

Methods

We searched Medline, Embase, PubMed databases, and the Cochrane Library. We systematically assessed randomized controlled trials (RCTs) evaluating dietary interventions on adults (mean BMI ≥ 25 kg/m2) receiving active dietary counseling for ≥12 months. We pooled the data using a random-effect NMA. We assessed the quality of the included RCTs using the Cochrane risk of bias (ROB) tool.

Results

We included 36 trials, 14 of which compared HFLC with MM diets. Compared with UD, all diets were associated with a significant weight loss (WL) at ≥12 months, HFLC [mean difference in kg (95% CI): −5.5 (−7.6; −3.4)], LFHC [−5.0 (−7.1; −2.9)] and MM [−4.7 (−6.8; −2.7)]. HFLC, compared with MM diet, was associated with a slightly higher WL (of −0.77 kg) and drop in BMI (of −0.36 kg/m2), while no significant difference was detected in other dietary comparisons. WC was lower with all diets compared to UD, with no significant difference across specific diets. There was no significant interaction of the results with the pre-specified sub-groups. The ROB was moderate to high, mostly related to unclear allocation concealment, high dropout rate and unclear or lack of blinding of participants, providers, and outcome assessors.

Conclusion

Dietary interventions extending over ≥12 months are superior to UD in inducing weight, BMI and WC loss. HFLC might be associated with a slightly higher WL compared with MM diets.

Systematic Trial Registration

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=103116, PROSPERO (CRD42018103116).
The Relationship Between Bone Mineral Density and Body Composition Among Qatari Women With High Rate of Obesity: Qatar Biobank Data
Authors: Kerkadi Abdelhamid , Lathief Shalima , Khial Yasmen , Teleb Toka , Attieh Grace , Rahman Md Mizanur , Shi Zumin , Agouni Abdelali
Published: April 2022

Studies have reported inconsistent results for the relationship between body composition and bone mineral density (BMD) among women, especially those with a high rate of obesity. This study aims to examine the association between BMD and body composition among Qatari women. A cross-sectional study, using data from the Qatar Biobank (QBB), was conducted on 2,000 Qatari women aged 18 and over. Measurements were taken by dual-energy X-ray absorptiometry (DEXA) for body composition [visceral fat and android fat (AF)], gynoid fat (GF), trunk fat, total fat mass (TFM), total lean mass (LM) and bone mineral density (BMD), including the lumber spine, neck, femur and total body. The participants were divided into groups of normal and low BMD, based on their T-score. Non-linear regression analysis using the restricted cubic spline method was performed according to the T-score of the total BMD for the fat mass variables. Women with a low BMD (T-score <-1) had significantly lower body composition indicators. LM was positively correlated with BMD at the spine (r = 0.29, p < 0.001), neck (r = 0.32, p < 0.001), and femur (r = 0.28, p < 0.001), as well as total BMD (r = 0.29, p < 0.001) and T-score (r = 0.31, p < 0.001), while the correlatio between TFM and BMD was negative and weak (r = −0.05, <0.017). Results of the non-linear regression indicated that components of fat distribution (TFM, AF, GF and trunk fat) were positively associated with total body T-score. In the adjusted non-liner regression, only a slight increase in T-score was recorded with an increase in FM. The association between FM and BMD was non-linear, suggesting that FM may not be a strong protector of bones among women with high rate of obesity.
Hepatoprotection of Probiotics Against Non-Alcoholic Fatty Liver Disease in vivo: A Systematic Review
Authors: Sabirin Faezah , Lim Siong Meng , Neoh Chin Fen , Ramasamy Kalavathy
Published: April 2022

Probiotic supplements have been increasingly reported for their usefulness in delaying the development and progression of non-alcoholic fatty liver disease (NAFLD). Literature on the impact of probiotics on NAFLD covered various aspects of the disease. This study was undertaken to systematically review in vivo findings on hepatoprotection of probiotics against NAFLD. The literature search was performed through Cochrane, PubMed/MEDLINE, Embase, and Web of Science databases. Interventions of known probiotics in NAFLD-induced animal model with at least one measurable NAFLD-related parameter were included. The data were extracted by all authors independently. Quality assessment was conducted using the Systematic Review Center for Laboratory animal Experimentation (SYRCLE's) Risk of Bias (RoB) tool. P-values of measures were compared inter- and intra-study for each parameter. Forty-four probiotic-based studies of NAFLD-induced rodents were shortlisted. The majority of the studies were presented with low/unclear risk of bias. Probiotics improved the histopathology of NAFLD rodents (primary outcome). Most of the probiotic-supplemented NAFLD rodents were presented with mixed effects on serum liver enzymes but with improved hepatic and serum lipid profiles (including increased serum high-density lipoprotein cholesterol). The findings were generally accompanied by downregulation of hepatic lipogenic, oxidative, and inflammatory signallings. Probiotics were found to modulate gut microbiota composition and its products, and intestinal permeability. Probiotics also resulted in better glycaemic control and reduced liver weight. Altogether, the present qualitative appraisals strongly implied the hepatoprotective potential of probiotics against NAFLD in vivo.
Maternal High-Fructose Intake Activates Myogenic Program in Fetal Brown Fat and Predisposes Offspring to Diet-Induced Metabolic Dysfunctions in Adulthood
Authors: Wang Peng , Wu Tian , Fu Qinghua , Liao Qichao , Li Yan , Huang Tengda , Li Yixing , Zhou Lei , Song Ziyi
Published: April 2022

Excess dietary fructose intake is a major public health concern due to its deleterious effect to cause various metabolic and cardiovascular diseases. However, little is known about the effects of high-fructose consumption during pregnancy on offspring metabolic health in adulthood. Here, we show that maternal consumption of 20% (w/v) fructose water during pregnancy does not alter the metabolic balance of offspring with a chow diet, but predisposes them to obesity, fatty liver, and insulin resistance when challenged by a high-fat diet. Mechanistically, diet-induced brown fat reprogramming and global energy expenditure in offspring of fructose-fed dams are impaired. RNA-seq analysis of the fetal brown fat tissue reveals that the myogenic pathway is predominantly upregulated in the fructose-treated group. Meanwhile, circulating fructose level is found to be significantly elevated in both fructose-fed dams and their fetuses. Importantly fructose gavage also acutely activates the myogenic program in mice brown fat. Together, our data suggest that maternal high-fructose intake impairs fetal brown fat development, resultantly attenuates diet-induced thermogenesis and causes metabolic disorders in adult offspring probably through inducing myogenic signature in brown fat at the fetal stage.
Food Intake and Diet Quality of Pregnant Women in China During the COVID-19 Pandemic: A National Cross-Sectional Study
Authors: Chen Haitian , Li Hailin , Cao Yinli , Qi Hongbo , Ma Yuyan , Bai Xiaoxia , Zhao Yangyu , Wu Li , Liu Caixia , Wei Jun , Wang Hong , Jin Yan , Wang Zilian , Zhu Yanna
Published: April 2022

Background:

Between January and April 2020, China implemented differentiated prevention and control strategies across the country, based on the severity of the COVID-19 epidemic/pandemic in different regions. These strategies included lockdowns, social distancing, and the closure of public places. These measures may have affected dietary intake to varying degrees. This study aimed to assess variations in food intake and diet quality among pregnant women according to regional severity and related control measures during the most severe period of COVID-19 restrictions in 2020.

Methods

A total of 3,678 pregnant women from 19 provinces/municipalities in mainland China were analyzed in this nationwide, multi-center study. Food intake data were obtained and assessed using a validated food frequency questionnaire (FFQ). Diet quality was quantified using the Diet Balance Index for Pregnancy (DBI-P), which included high bound score (HBS, excessive dietary intake), low bound score (LBS, insufficient dietary intake), and diet quality distance (DQD, dietary imbalance). Linear trend tests and multivariable regression analyses were performed to examine the association between food intake, DBI-P and the severity of pandemic.

Results

The median daily intake of vegetables, fruit, livestock/poultry meat, dairy, and nuts decreased (p < 0.05) according to low, moderate, and high severity of the pandemic, while no significant differences in cereals/potatoes, eggs, and fish/shrimp intake. The median daily intake of cereals/potatoes exceeded the recommended ranges, and the daily intake of eggs and fish/shrimp was below recommended ranges regardless of the pandemic severity (p < 0.05). Regarding diet quality, HBS decreased (lower excessive consumption) (p = 0.047) and LBS increased (greater insufficient consumption) (p = 0.046) with increased severity of the pandemic. On multivariable analyses, moderate and high pandemic severity were related to lower HBS risk (OR = 0.687, OR = 0.537) and higher LBS risk (β = 1.517, β = 3.020) when compared to low pandemic severity.

Conclusions

Under more severe COVID-19 pandemic conditions, pregnant women consumed less quality food, characterized by reduced consumption of vegetables, fruit, livestock/poultry meat, dairy and nuts, while the quality of the foods that pregnant women consumed in excess tended to improve, but the overconsumption of cereals/potatoes was a problem.
Diet Quality Scores and Asthenoteratozoospermia Risk: Finding From a Hospital-Based Case–Control Study in China
Authors: Cui Qi , Wang Hui-Han , Wu Qi-Jun , Wang Xiao-Bin , Guo Ren-Hao , Leng Xu , Tan Xiao-Ling , Du Qiang , Pan Bo-Chen
Published: April 2022

Objective

We aimed to examine associations of diet quality scores, including the dietary approaches to stop hypertension (DASH), alternate Healthy Eating Index (AHEI), and Chinese Healthy Eating Index (CHEI) with asthenoteratozoospermia risk in China.

Methods

Among 254 cases and 633 controls in a hospital-based case–control study in Shenyang, Liaoning Province, China, DASH, AHEI, and CHEI were calculated using a validated food frequency questionnaire. Asthenotetrazoospermia was evaluated according to World Health Organization guidelines. Unconditional multiple logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between quality diet scores and asthenoteratozoospermia risk.

Results

We found that the CHEI score was inversely associated with asthenoteratozoospermia risk, with ORs of 0.59 (95% CI 0.39, 0.88) and 0.59 (95% CI 0.39, 0.88) for the 2nd and 3rd tertiles vs. the 1st tertile, respectively (P trend < 0.05). In addition, our data indicated that each standard deviation increase in CHEI, AHEI-2010, and DASH score was associated with 19, 13, and 17% decreased risk of asthenoteratozoospermia, respectively.

Conclusion

Our findings suggest that higher adherence to the CHEI, AHEI-2010, and DASH diet quality scores may reduce the risk of asthenoteratozoospermia, especially for younger participants.
Freshwater Macrophytes: A Potential Source of Minerals and Fatty Acids for Fish, Poultry, and Livestock
Authors: Kumar Guddu , Sharma JaiGopal , Goswami Ravi Kumar , Shrivastav Avanish Kumar , Tocher Douglas R. , Kumar Neelesh , Chakrabarti Rina
Published: April 2022

The freshwater macrophytes are abundant in tropical and subtropical climates. These macrophytes may be used as feed ingredients for fish and other animals. The nutritional value of twelve freshwater-cultured macrophytes was evaluated in the present study. Significantly higher crude protein (36.94–36.65%) and lipid (8.13–7.62%) were found in Lemna minor and Spirodela polyrhiza; ash content was significantly higher in Hydrilla verticillata, Wolffia globosa, and Pistia stratiotes (20.69–21.00%) compared with others. The highest levels of sodium, magnesium, chromium, and iron levels were recorded in P. stratiotes. H. verticillata was a rich source of copper, manganese, cobalt, and zinc; the contents of calcium, magnesium, strontium, and nickel were highest in S. polyrhiza. Selenium and potassium contents were higher in Salvinia natans and W. globosa, respectively. The n-6 and n-3 polyunsaturated fatty acids (PUFAs) contents were significantly higher in W. globosa and Ipomoea aquatica, respectively compared with others. Linoleic and α-linolenic acids were dominant n-6 and n-3 PUFAs. The highest value (4.04) of n-3/n-6 was found in I. aquatica. The ratio ranged from 0.61 to 2.46 in other macrophytes. This study reveals that macrophytes are rich sources of minerals, n-6 and n-3 PUFAs.
Post-harvest Application of Methyl Jasmonate or Prohydrojasmon Affects Color Development and Anthocyanins Biosynthesis in Peach by Regulation of Sucrose Metabolism
Authors: Tang Tingting , Zhou Hongsheng , Wang Libin , Zhao Jing , Ma Lijie , Ling Jun , Li Guofeng , Huang Wen , Li Pengxia , Zhang Yingtong
Published: April 2022

The roles of methyl jasmonate (MeJA) and prohydrojasmon (PDJ) in postharvest color development and anthocyanins biosynthesis in the skin of peach fruit remain unclear. In this study, peach fruit were infiltrated with MeJA (200 μM) or PDJ (40 μM) and stored at 22°C for 7 days. The results showed that treatment with MeJA or PDJ had a positive effect on red color formation in peach fruits due to anthocyanins accumulation (∼120% increase). This was attributed to increased enzyme activities, and enhanced transcript abundance of the genes associated with anthocyanins biosynthesis, induced by MeJA or PDJ. Both MeJA and PDJ promoted sucrose biosynthesis, and the subsequently elevated levels of the sucrose during storage were positively correlated with anthocyanins accumulation (0.49) and the activities of key biosynthesis enzymes (0.42–0.79). Based on these findings, we proposed that MeJA or PDJ treatments promote anthocyanins biosynthesis by regulating sucrose metabolism during the postharvest storage of peach fruit.
Influence of Carboxymethyl Cellulose on the Stability, Rheological Property, and in-vitro Digestion of Soy Protein Isolate (SPI)-Stabilized Rice Bran Oil Emulsion
Authors: Zhang Wenguan , Hao Jia , Yuan Yanan , Xu Duoxia
Published: April 2022

In this study, carboxymethyl cellulose (CMC) was added to soybean protein isolate (SPI)-stabilized rice bran oil (RBO) emulsion to improve its physicochemical stability and free fatty acid (FFA) release characteristics. RBO emulsions stabilized by SPI and various contents of CMC were prepared and assessed by measuring zeta potential, particle size, transmission, and microstructure, the rheological properties were analyzed by dynamic shear rheometer. In addition, its chemical stability was characterized by a storage experiment, and the FFA release was explored by a simulated gastrointestinal tract (GIT) model. It showed that the negative charge of the droplets of RBO emulsion was increased with increasing CMC content. The decrease in transmission of SPI-stabilized RBO emulsion with increasing CMC content was due to the droplets not being free to move by the special network interaction and an increase in the viscosity. According to the determination of the reactive substances of lipid hydroperoxide and thiobarbituric acid during 30 days storage at 37°C, the chemical stability of the emulsion added with CMC was enhanced compared with the SPI-stabilized RBO emulsion. In-vitro digestion studies not only evaluated the structural changes of RBO emulsions at different stages, but also found that RBO emulsion with CMC showed a higher level of free fatty acids release in comparison with that without CMC. It indicated that the utilization of CMC can improve the bioavailability of RBO emulsions.
Baseline Mutations and Up-Regulation of PI3K-AKT Pathway Serve as Potential Indicators of Lack of Response to Neoadjuvant Chemotherapy in Stage II/III Breast Cancer
Authors: Dong Menghao , Shan Benjie , Han Xinghua , Zhao Xiaotian , Wang Fufeng , Zhu Liuqing , Ou Qiuxiang , Ma Xiaopeng , Pan Yueyin
Published: April 2022

Background

Neoadjuvant chemotherapy (NAC) has been expanded to hormone receptor (HR) positive breast cancer (BC) patients with operable disease, to increase the likelihood of breast-conserving surgery. Genomic profiling at baseline would reveal NAC response relevant genomic features and signaling pathways, guiding clinical NAC utilization based on patients’ genomic characteristics.

Methods

We prospectively studied stage II/III BC patients who were eligible for breast-conserving surgery. Patients received epirubicin and cyclophosphamide for 4 cycles, followed by another 4-cycle docetaxel, and human epidermal growth factor receptor (HER2) positive patients were additionally treated with herceptin when using docetaxel (EC-T(H)). NAC responses were evaluated as pathologic complete response (pCR) or non-pathologic complete response (non-pCR). Genomic features related to NAC responses were identified by profiling baseline tumor tissues sampled one day before NAC, using whole-exome sequencing. Differentially expressed genes and up-/down-regulated pathways were investigated by performing RNA-sequencing.

Results

A total of 25 stage II/III BC patients were enrolled, including 5 patients ultimately evaluated as pCR and 20 patients evaluated as non-pCR. PIK3CA (48%) and TP53 (40%) mutations were enriched in patients not achieving pCR. Mutated phosphatidylinositol-3-kinase-AKT (PI3K-AKT) pathway and homologous recombinational repair pathway were also more frequently observed in patients evaluated as non-pCR. Significant arm-level amplifications (8q24.23 and 17q12) and deletions (1p32.2, 4p14, 7q11.23, 10q21.3, 11q23.3, etc.) were identified among patients not achieving pCR, while patients achieving pCR displayed no significant copy number alterations. Significantly up-regulated expression of PI3K-AKT pathway genes was also detected among patients failed to achieve pCR, compared to patients achieving pCR.

Conclusion

Compared to BC patients achieving pCR to NAC, aberrant activation of PI3K-AKT pathway genes were more frequently observed in patients not achieving pCR, consistent with the significant up-regulation of PI3K-AKT pathway gene expression in the non-pCR subgroup. Together, these findings indicate that upregulated PI3K-AKT pathway serves as a potential indicator of lack of response to NAC in stage II/III BC patients, and other effective therapeutic options are urgently needed for those resistant patients.
Bacteria-Mediated Oncogenesis and the Underlying Molecular Intricacies: What We Know So Far
Authors: Prasad Shashanka K. , Bhat Smitha , Shashank Dharini , C. R. Akshatha , R. Sindhu , Rachtanapun Pornchai , Devegowda Devananda , Santhekadur Prasanna K. , Sommano Sarana Rose
Published: April 2022

Cancers are known to have multifactorial etiology. Certain bacteria and viruses are proven carcinogens. Lately, there has been in-depth research investigating carcinogenic capabilities of some bacteria. Reports indicate that chronic inflammation and harmful bacterial metabolites to be strong promoters of neoplasticity. Helicobacter pylori-induced gastric adenocarcinoma is the best illustration of the chronic inflammation paradigm of oncogenesis. Chronic inflammation, which produces excessive reactive oxygen species (ROS) is hypothesized to cause cancerous cell proliferation. Other possible bacteria-dependent mechanisms and virulence factors have also been suspected of playing a vital role in the bacteria-induced-cancer(s). Numerous attempts have been made to explore and establish the possible relationship between the two. With the growing concerns on anti-microbial resistance and over-dependence of mankind on antibiotics to treat bacterial infections, it must be deemed critical to understand and identify carcinogenic bacteria, to establish their role in causing cancer.
WTAP Is Correlated With Unfavorable Prognosis, Tumor Cell Proliferation, and Immune Infiltration in Hepatocellular Carcinoma
Authors: Liang Linjun , Xu Hongfa , Dong Qichao , Qiu Lige , Lu Ligong , Yang Qing , Zhao Wei , Li Yong
Published: April 2022

WTAP is involved in various pathological and physiological processes, but its function in hepatocellular carcinoma (HCC) remains elusive. In this study, we investigated the role of WTAP in HCC. Firstly, the mRNA and protein of WTAP were expressed highly in HCC tissue, which reflected clinicopathological characteristics of HCC patients. Then, an interactive analysis of genetic profiles and Kaplan–Meier curves was performed to show that WTAP was an independent predictor of survival of HCC patients. Meanwhile, genes co-expressed with WTAP, potential protein–protein interactions, related signaling pathways, and immune cell infiltration were identified. It was found that high WTAP expression correlated with enhanced interactions between cytokines and their receptors, cell cycle, and chemokine signaling pathways, as well as increased immune cell infiltration. At last, WTAP knockdown experiments in vitro indicate that the WTAP silencing inhibited HCC proliferation and aggressiveness. We conclude that WTAP may be a novel biomarker for prognosis and a therapeutic target for HCC.
Prognostic Impacts of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Acute Coronary Syndrome Patients Without Heart Failure
Authors: Chen Runzhen , Liu Chen , Zhou Peng , Li Jiannan , Zhou Jinying , Wang Ying , Zhao Xiaoxiao , Chen Yi , Yan Shaodi , Song Li , Zhao Hanjun , Yan Hongbing
Published: April 2022

Background: Despite the recommendations from mainstream guidelines, the use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) for acute coronary syndrome (ACS) patients without heart failure (HF) is controversial, as its evidence is lacking in the era of reperfusion and intensive secondary preventions. This study aimed to investigate the impacts of ACEI/ARB on outcomes of ACS patients without HF treated by percutaneous coronary intervention (PCI).

Methods: A total of 2,397 non-HF ACS patients treated by PCI were retrospectively recruited. Prognostic impacts of ACEI/ARB were assessed by unadjusted analysis, followed by propensity score matching (PSM) and propensity score matching weight (PSMW) analysis to control the between-group differences. The primary outcome was a composite of all-cause death and recurrent myocardial infarction (MI).

Results: Among the included patients, 1,805 (75.3%) were prescribed with ACEI/ARB at discharge. The median follow-up time was 727 (433–2016) days, with 129 (5.4%) primary endpoint events, consisting of 55 (2.3%) cases of all-cause death and 74 (3.1%) cases of recurrent MI. The use of ACEI/ARB was not associated with significant risk reduction of primary endpoint events in unadjusted analysis (hazard ratio [HR]: 0.95, 95% confidence interval [CI]: 0.64–1.39, p = 0.779), PSM analysis (HR: 0.94, 95% CI: 0.60–1.47, p = 0.784), and PSMW analysis (HR: 0.91, 95% CI: 0.55–1.49, p = 0.704). Similar results were observed for secondary outcomes of all-cause death, cardiac death, and recurrent MI.

Conclusion: For ACS patients without HF, the use of ACEI/ARB was not associated with lower risk of death or recurrent MI after PCI.
Cyclic GMP and PKG Signaling in Heart Failure
Authors: Numata Genri , Takimoto Eiki
Published: April 2022

Cyclic guanosine monophosphate (cGMP), produced by guanylate cyclase (GC), activates protein kinase G (PKG) and regulates cardiac remodeling. cGMP/PKG signal is activated by two intrinsic pathways: nitric oxide (NO)-soluble GC and natriuretic peptide (NP)-particulate GC (pGC) pathways. Activation of these pathways has emerged as a potent therapeutic strategy to treat patients with heart failure, given cGMP-PKG signaling is impaired in heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). Large scale clinical trials in patients with HFrEF have shown positive results with agents that activate cGMP-PKG pathways. In patients with HFpEF, however, benefits were observed only in a subgroup of patients. Further investigation for cGMP-PKG pathway is needed to develop better targeting strategies for HFpEF. This review outlines cGMP-PKG pathway and its modulation in heart failure.
Effects of a Single Sub-Anesthetic Dose of Ketamine on Postoperative Emotional Responses and Inflammatory Factors in Colorectal Cancer Patients
Authors: Ren Qin , Hua Ling , Zhou Xiaofang , Cheng Yong , Lu Mingjun , Zhang Chuanqing , Guo Jianrong , Xu Hua
Published: April 2022

Objective: To investigate the effect of a single sub-anesthetic dose of ketamine on postoperative anxiety, depression, and inflammatory factors in patients with colorectal cancer.

Methods: A total of 104 patients undergoing selective colorectal surgery in our hospital from Jan 2015 to Oct 2017 were included and randomly assigned (1:1:1:1) into a 0.1 mg kg−1 ketamine group (K1 group), 0.2 mg kg−1 ketamine group (K2 group), 0.3 mg kg−1 ketamine group (K3 group), or control group (C group). Corresponding doses of ketamine were given intravenously in the K groups (K1, K2, and K3 groups) 5 min before operation, and the same amount of normal saline was given in the C group. The intravenous analgesia program was identical in the four groups. The patients’ emotional reactions (anxiety and depression) were assessed by the Hospital Anxiety and Depression Scale (HAD), the quality of postoperative recovery was evaluated by the Quality of Recovery-40 (QoR-40) questionnaire, and the levels of IL-6, IL-8, and TNF-α in peripheral blood were detected by enzyme-linked immunosorbent assay (ELISA) on the day before operation and within 24, 48, and 72 h post-operation respectively. Pain was estimated by the visual analog scale (VAS), and sedation was assessed with Ramsay score 30 min after extubation. The time points of anesthetic end and extubation were recorded. The complications during anesthesia and recovery such as cough and agitation 30 min after extubation were recorded.

Results: The anxiety score (HAD-A) and depression score (HAD-D) of the K3 group were significantly lower than those of the C group post-operation (p < 0.05). The QoR-40 score of the K3 group was significantly higher than that of the C group (p < 0.05). The serum levels of IL-6, IL-8, and TNF-α in the K3 group were significantly lower than those in the C group (p < 0.05 and p < 0.01). There were no significant differences in HAD-A, HAD-D, and QoR-40 scores or serum levels of IL-6, IL-8, and TNF-α between the K1 and K2 groups and the C group. There were no significant differences in VAS pain score or Ramsay sedation score among the four groups 30 min after extubation. There were no significant differences in extubation time, postoperative cough, emergence agitation, or delirium among the four groups. Dizziness, nausea, vomiting, diplopia, or other adverse reactions were not found 30 min after extubation.

Conclusion: A single sub-anesthetic dose (0.3 mg kg−1) of ketamine can significantly improve the postoperative anxiety and depression of colorectal cancer patients and reduce the levels of IL-6, IL-8, and TNF-α.
Title: P2x7 Receptor Activation and Estrogen Status Drive Neuroinflammatory Mechanisms in a Rat Model for Dry Eye
Authors: Bereiter David A. , Rahman Mostafeezur , Ahmed Fabeeha , Thompson Randall , Luong Nhungoc , Olson Julie K.
Published: April 2022

Dry eye disease (DED) is recognized as a chronic inflammatory condition with an increase in tear osmolarity and loss of tear film integrity. DED is often accompanied by adverse ocular symptoms which are more prevalent in females than males. The basis for ocular hyperalgesia in DED remains uncertain; however, both peripheral and central neural mechanisms are implicated. A model for aqueous deficient DED, exorbital gland excision, was used to determine if activation of the purinergic receptor subtype 7, P2X7R, expressed by non-neural cells in peripheral and central trigeminal nerve pathways, contributed to persistent ocular hyperalgesia. Densitometry of trigeminal brainstem sections revealed increases in P2X7R, the myeloid cell marker Iba1, and the inflammasome, NLRP3, of estradiol-treated DED females compared to estradiol-treated sham females, while expression in DED males and DED females not given estradiol displayed minor changes. No evidence of immune cell infiltration into the trigeminal brainstem was seen in DED rats; however, markers for microglia activation (Iba1) were increased in all groups. Isolated microglia expressed increased levels of P2X7R and P2X4R, IL-1β (Ιnterleukin-1β), NLRP3, and iNOS (nitric oxide synthase). Further, estradiol-treated DED females displayed greater increases in P2X7R, IL-1β and NLRP3 expression compared to untreated DED females. Orbicularis oculi muscle activity (OOemg) evoked by ocular instillation of hypertonic saline (HS) was recorded as a surrogate measure of ocular hyperalgesia and was markedly enhanced in all DED groups compared to sham rats. Systemic minocycline reduced HS-evoked OOemg in all DED groups compared to sham rats. Local microinjection in the caudal trigeminal brainstem of an antagonist for P2X7R (A804598) greatly reduced HS-evoked OOemg activity in all DE groups, while responses in sham groups were not affected. Intra-trigeminal ganglion injection of siRNA for P2X7R significantly reduced HS-evoked OOemg activity in all DED groups, while evoked responses in sham animals were not affected. These results indicated that activation of P2X7R at central and peripheral sites in trigeminal pain pathways contributed to an increase in ocular hyperalgesia and microglia activation in DED males and females. Estrogen treatment in females further amplified ocular hyperalgesia and neuroimmune responses in this model for aqueous deficient DED.
Integrated Metabolomics and Network Pharmacology Analysis Immunomodulatory Mechanisms of Qifenggubiao Granules
Authors: Guo Bindan , Dong Wenting , Huo Jinhai , Sun Guodong , Qin Zhiwei , Liu Xiaodong , Zhang Bihai , Wang Weiming
Published: April 2022

Background: Qifenggubiao granules (QFGBG) is a new Chinese medicine independently developed by Heilongjiang Academy of Traditional Chinese Medicine, which combines the essence of Yupingfeng powder and Shengmai yin (invention patent number: CN1325098C, approval number: Sinopharm Zhunzi B20020410), and has been included in the 2020 edition of Chinese Pharmacopoeia. It has remarkable pharmacodynamic results and conclusive clinical effects in the treatment of allergic rhinitis, chronic cough and other diseases. Previous pharmacological studies have shown that it has immunomodulatory effect, but its immunomodulatory mechanism is still unclear.

Methods: In this study, cyclophosphamide (CTX) was used to establish the immune hypofunction model in mice, and the weight change, index of immune organs in spleen and thymus, pathological sections of immune organs and inflammatory factors were used to evaluate the model. Based on the metabolic biomarkers obtained by metabonomics technology, the potential targets of Qifeng Gubiao Granule immunomodulation were obtained by integrating the targets of blood components, metabolites and diseases through network pharmacology. Meanwhile, GO enrichment analysis and KEGG pathway analysis were carried out on the potential targets.

Results: QFGBG can increase body weight and organ index, and recover immune organ damage caused by CP. Metabonomics identified 13 metabolites with significant changes, among which the level of phospholipid (PC) metabolites decreased significantly in the model group. Sphingosine -1- phosphate, 1- palmitoyl phosphatidylcholine [LysoPC (16:0/0:0)] and other metabolites were significantly increased in the model group, and 98 targets of Qifeng’s external immune regulation were obtained by intersecting 629 component targets, 202 metabolite targets and 1916 disease targets. KEGG pathway analysis obtained 233 related metabolic pathways, and the top 20 metabolic pathways mainly involved IL-17 signaling pathway, TNF signaling pathway, Sphingolipid signaling pathway, and so on.

Conclusion: QFGBG may act on AKT1, IL6, MAPK3, PTGS2, CASP3, MAPK1, ESR1, PPARG, HSP90AA1, PPARA and other targets, acting through Sphingolipid signaling pathway and signaling pathway. Combined with pharmacodynamic evaluation, the immunomodulatory effect of QFGBG was confirmed, and the immunomodulatory mechanism of QFGBG with multiple targets and multiple pathways was preliminarily clarified.
Dosage Strategy of Linezolid According to the Trough Concentration Target and Renal Function in Chinese Critically Ill Patients
Authors: Wu Fan , Zhang Xiao-Shan , Dai Ying , Zhou Zi-Ye , Zhang Chun-Hong , Han Lu , Xu Fang-Min , Wang Ye-Xuan , Shi Da-Wei , Lin Guan-Yang , Yu Xu-Ben , Chen Fang
Published: April 2022

Background: Linezolid is associated with myelosuppression, which may cause failure in optimally treating bacterial infections. The study aimed to define the pharmacokinetic/toxicodynamic (PK/TD) threshold for critically ill patients and to identify a dosing strategy for critically ill patients with renal insufficiency.

Methods: The population pharmacokinetic (PK) model was developed using the NONMEM program. Logistic regression modeling was conducted to determine the toxicodynamic (TD) threshold of linezolid-induced myelosuppression. The dosing regimen was optimized based on the Monte Carlo simulation of the final model.

Results: PK analysis included 127 linezolid concentrations from 83 critically ill patients at a range of 0.25–21.61 mg/L. Creatinine clearance (CrCL) was identified as the only covariate of linezolid clearance that significantly explained interindividual variability. Thirty-four (40.97%) of the 83 patients developed linezolid-associated myelosuppression. Logistic regression analysis showed that the trough concentration (Cmin) was a significant predictor of myelosuppression in critically patients, and the threshold for Cmin in predicting myelosuppression with 50% probability was 7.8 mg/L. The Kaplan–Meier plot revealed that the overall median time from the initiation of therapy to the development of myelosuppression was 12 days. Monte Carlo simulation indicated an empirical dose reduction to 600 mg every 24 h was optimal to balance the safety and efficacy in critically ill patients with CrCL of 30–60 ml/min, 450 mg every 24 h was the alternative for patients with CrCL <30 ml/min, and 600 mg every 12 h was recommended for patients with CrCL ≥60 ml/min.

Conclusion: Renal function plays a significant role in linezolid PKs for critically ill patients. A dose of 600 mg every 24 h was recommended for patients with CrCL <60 ml/min to minimize linezolid-induced myelosuppression.
Chronic Allergen Challenge Induces Corticosteroid Insensitivity With Persistent Airway Remodeling and Type 2 Inflammation
Authors: Lewis Brandon W. , Ford Maria L. , Khan Aiman Q. , Walum Joshua , Britt Rodney D.
Published: April 2022

Type 2-high severe asthma is described as a distinct endotype with Th2 inflammation, high eosinophil lung infiltration, impaired lung function, and reduced corticosteroid sensitivity. While the inflammatory milieu is similar to mild asthma, patients with type 2-high severe asthma likely have underlying mechanisms that sustain asthma pathophysiology despite corticosteroid treatments. Acute and chronic allergen models induce robust type 2 inflammatory responses, however differences in corticosteroid sensitivity remains poorly understood. In the present study, we sensitized and challenged mice with ovalbumin (OVA; acute model) or mixed allergens (MA; chronic model). Corticosteroid sensitivity was assessed by administering vehicle, 1, or 3 mg/kg fluticasone propionate (FP) and examining key asthmatic features such as airway inflammation, remodeling, hyperresponsiveness, and antioxidant capacity. Both acute and chronic allergen exposure exhibited enhanced AHR, immune cell infiltration, airway inflammation, and remodeling, but corticosteroids were unable to fully alleviate inflammation, AHR, and airway smooth muscle mass in MA-challenged mice. While there were no differences in antioxidant capacity, persistent IL-4+ Th2 cell population suggests the MA model induces type 2 inflammation that is insensitive to corticosteroids. Our data indicate that chronic allergen exposure is associated with more persistent type 2 immune responses and corticosteroid insensitivity. Understanding differences between acute and chronic allergen models could unlock underlying mechanisms related to type 2-high severe asthma.
Identification of a DNA Damage Response and Repair-Related Gene-Pair Signature for Prognosis Stratification Analysis in Hepatocellular Carcinoma
Authors: Chen Yi , Huang Mengjia , Zhu Junkai , Xu Li , Cheng Wenxuan , Lu Xiaofan , Yan Fangrong
Published: April 2022

Background: Nowadays, although the cause of hepatocellular carcinoma (HCC) mortality and recurrence remains at a high level, the 5-year survival rate is still very low. The DNA damage response and repair (DDR) pathway may affect HCC patients’ survival by influencing tumor development and therapeutic response. It is necessary to identify a prognostic DDR-related gene signature to predict the outcome of patients.

Methods: Level 3 mRNA expression and clinical information were extracted from the TCGA website. The GSE14520 datasets, ICGC-LIRI datasets, and a Chinese HCC cohort were served as validation sets. Univariate Cox regression analysis and LASSO-penalized Cox regression analysis were performed to construct the DDR-related gene pair (DRGP) signature. Kaplan–Meier survival curves and time-dependent receiver operating characteristic (ROC) analysis curves were calculated to determine the predictive ability of this prognostic model. Then, a prognostic nomogram was established to help clinical management. We investigated the difference in biological processes between HRisk and LRisk by conducting several enrichment analyses. The TIDE algorithm and R package “pRRophetic” were applied to estimate the immunotherapeutic and chemotherapeutic response.

Results: We constructed the prognostic signature based on 23 DDR-related gene pairs. The patients in the training datasets were divided into HRisk and LRisk groups at median cut-off. The HRisk group had significantly poorer OS than the LRisk group, and the signature was an independent prognostic indicator in HCC. Furthermore, a nomogram of the riskscore combined with TNM stage was constructed and detected by the calibration curve and decision curve. The LRisk group was associated with higher expression of HBV oncoproteins and metabolism pathways, while DDR-relevant pathways and cell cycle process were enriched in the HRisk group. Moreover, patients in the LRisk group may be more beneficial from immunotherapy. We also found that TP53 gene was more frequently mutated in the HRisk group. As for chemotherapeutic drugs commonly used in HCC, the HRisk group was highly sensitive to 5-fluorouracil, while the LRisk group presented with a significantly higher response to gefitinib and gemcitabine.

Conclusion: Overall, we developed a novel DDR-related gene pair signature and nomogram to assist in predicting survival outcomes and clinical treatment of HCC patients. It also helps understand the underlying mechanisms of different DDR patterns in HCC.