bluuebunny/crossref_metadata_2025 huggingface dataset:
3D FRN-ResNet: An Automated Major Depressive Disorder Structural Magnetic Resonance Imaging Data Identification Framework
Authors: Hong Jialin , Huang Yueqi , Ye Jianming , Wang Jianqing , Xu Xiaomei , Wu Yan , Li Yi , Zhao Jialu , Li Ruipeng , Kang Junlong , Lai Xiaobo
Published: May 2022

Major Depressive Disorder (MDD) is the most prevalent psychiatric disorder, seriously affecting people’s quality of life. Manually identifying MDD from structural magnetic resonance imaging (sMRI) images is laborious and time-consuming due to the lack of clear physiological indicators. With the development of deep learning, many automated identification methods have been developed, but most of them stay in 2D images, resulting in poor performance. In addition, the heterogeneity of MDD also results in slightly different changes reflected in patients’ brain imaging, which constitutes a barrier to the study of MDD identification based on brain sMRI images. We propose an automated MDD identification framework in sMRI data (3D FRN-ResNet) to comprehensively address these challenges, which uses 3D-ResNet to extract features and reconstruct them based on feature maps. Notably, the 3D FRN-ResNet fully exploits the interlayer structure information in 3D sMRI data and preserves most of the spatial details as well as the location information when converting the extracted features into vectors. Furthermore, our model solves the feature map reconstruction problem in closed form to produce a straightforward and efficient classifier and dramatically improves model performance. We evaluate our framework on a private brain sMRI dataset of MDD patients. Experimental results show that the proposed model exhibits promising performance and outperforms the typical other methods, achieving the accuracy, recall, precision, and F1 values of 0.86776, 0.84237, 0.85333, and 0.84781, respectively.
Surprising Threats Accelerate Conscious Perception
Authors: McFadyen Jessica , Tsuchiya Naotsugu , Mattingley Jason B. , Garrido Marta I.
Published: May 2022

The folk psychological notion that “we see what we expect to see” is supported by evidence that we become consciously aware of visual stimuli that match our prior expectations more quickly than stimuli that violate our expectations. Similarly, “we see what we want to see,” such that more biologically-relevant stimuli are also prioritised for conscious perception. How, then, is perception shaped by biologically-relevant stimuli that we did not expect? Here, we conducted two experiments using breaking continuous flash suppression (bCFS) to investigate how prior expectations modulated response times to neutral and fearful faces. In both experiments, we found that prior expectations for neutral faces hastened responses, whereas the opposite was true for fearful faces. This interaction between emotional expression and prior expectations was driven predominantly by participants with higher trait anxiety. Electroencephalography (EEG) data collected in Experiment 2 revealed an interaction evident in the earliest stages of sensory encoding, suggesting prediction errors expedite sensory encoding of fearful faces. These findings support a survival hypothesis, where biologically-relevant fearful stimuli are prioritised for conscious access even more so when unexpected, especially for people with high trait anxiety.
Research on the Contour Modeling Method of Peripheral Nerve Internal Fascicular Groups During the Non-Splitting/Merging Phase and Distribution Rules of Model Parameters
Authors: Zhong Yingchun , Tian Zhihao , Luo Peng , Sun Siyu , Zhu Shuang
Published: May 2022

Objectives

To investigate benchmark data for docking the same functional nerve bundles based on the mathematical contour model of peripheral nerve internal fascicular groups.

Materials and Methods

First, the discrete points of the original contours of nerve bundles were extracted into a dataset through the image process. Second, two indicators were employed to evaluate the modeling precision. Third, the dataset was modeled by the 3rd-order quasi-uniform B-spline method. Fourth, the dataset was modeled by the Fourier transform method. Fifth, all contours were modeled by the 4th-order Fourier method. Then, the histogram of each parameter from the Fourier model was calculated. Furthermore, the probability density function was fit to each parameter.

Results

First, the optimized sampling number of the 3rd-order quasi-uniform B-spline method is 21. The sampling number is the control point number of the 3rd-order quasi-uniform B-spline, which produces more than 63 parameters in the model. Second, when the Fourier transform model is employed to model the contour of nerve bundles, the optimized order number yields a 4th-order Fourier model, which has 16 parameters. Third, when all contours are modeled by the 4th-order Fourier model, the statistical analysis shows that (1) the pitch parameters a1 and d1 obey the mixed Gaussian distribution; (2) the harmonic parameter b3 obeys the normal distribution; and (3) the pitch parameters b1 and c1 and the remaining harmonic parameters obey the t distribution with position and scale.

Conclusion

This work paves the way for the exploration of the correlation between model parameters and spatial extension.
Moyamoya Disease With Initial Ischemic or Hemorrhagic Attack Shows Different Brain Structural and Functional Features: A Pilot Study
Authors: Hu Junwen , Li Yin , Tong Yun , Li Zhaoqing , Chen Jingyin , Cao Yang , Zhang Yifan , Xu Duo , Zheng Leilei , Bai Ruiliang , Wang Lin
Published: May 2022

Objective

Cerebral ischemia and intracranial hemorrhage are the two main phenotypes of moyamoya disease (MMD). However, the pathophysiological processes of these two MMD phenotypes are still largely unknown. Here, we aimed to use multimodal neuroimaging techniques to explore the brain structural and functional differences between the two MMD subtypes.

Methods

We included 12 patients with ischemic MMD, 10 patients with hemorrhagic MMD, and 10 healthy controls (HCs). Each patient underwent MRI scans and cognitive assessment. The cortical thickness of two MMD subtypes and HC group were compared. Arterial spin labeling (ASL) and diffusion tensor imaging (DTI) were used to inspect the cerebral blood flow (CBF) of cortical regions and the integrity of related white matter fibers, respectively. Correlation analyses were then performed among the MRI metrics and cognitive function scores.

Results

We found that only the cortical thickness in the right middle temporal gyrus (MTG) of hemorrhagic MMD was significantly greater than both ischemic MMD and HC (p < 0.05). In addition, the right MTG showed higher ASL-CBF, and its associated fiber tract (arcuate fasciculus, AF) exhibited higher fractional anisotropy (FA) values in hemorrhagic MMD. Furthermore, the cortical thickness of the right MTG was positively correlated with its ASL-CBF values (r = 0.37, p = 0.046) and the FA values of right AF (r = 0.67, p < 0.001). At last, the FA values of right AF were found to be significantly correlated with cognitive performances within patients with MMD.

Conclusions

Hemorrhagic MMD shows increased cortical thickness on the right MTG in comparison with ischemic MMD and HCs. The increased cortical thickness is associated with the higher CBF values and the increased integrity of the right AF. These findings are important to understand the clinical symptoms and pathophysiology of MMD and further applied to clinical practice.
Cognitive Impact of Deep Brain Stimulation in Parkinson’s Disease Patients: A Systematic Review
Authors: Rački Valentino , Hero Mario , Rožmarić Gloria , Papić Eliša , Raguž Marina , Chudy Darko , Vuletić Vladimira
Published: May 2022

Introduction

Parkinson’s disease (PD) patients have a significantly higher risk of developing dementia in later disease stages, leading to severe impairments in quality of life and self-functioning. Questions remain on how deep brain stimulation (DBS) affects cognition, and whether we can individualize therapy and reduce the risk for adverse cognitive effects. Our aim in this systematic review is to assess the current knowledge in the field and determine if the findings could influence clinical practice.

Methods

We have conducted a systematic review according to PRISMA guidelines through MEDLINE and Embase databases, with studies being selected for inclusion via a set inclusion and exclusion criteria.

Results

Sixty-seven studies were included in this systematic review according to the selected criteria. This includes 6 meta-analyses, 18 randomized controlled trials, 17 controlled clinical trials, and 26 observational studies with no control arms. The total number of PD patients encompassed in the studies cited in this review is 3677, not including the meta-analyses.

Conclusion

Cognitive function in PD patients can deteriorate, in most cases mildly, but still impactful to the quality of life. The strongest evidence is present for deterioration in verbal fluency, while inconclusive evidence is still present for executive function, memory, attention and processing speed. Global cognition does not appear to be significantly impacted by DBS, especially if cognitive screening is performed prior to the procedure, as lower baseline cognitive function is connected to poor outcomes. Further randomized controlled studies are required to increase the level of evidence, especially in the case of globus pallidus internus DBS, pedunculopontine nucleus DBS, and the ventral intermediate nucleus of thalamus DBS, and more long-term studies are required for all respective targets.
Acute Alcohol Intake Affects Internal Additive Noise and the Perceptual Template in Visual Perception
Authors: Zhang Pan , Guo Yeshuo , Qiao Yuxin , Yan Nan , Zhang Yajing , Ren Weicong , Zhang Shilei , Wu Di
Published: May 2022

A reduction in visual performance is among the serious consequences of acute alcohol intake. Contrast sensitivity (CS) is a fundamental feature of visual function. Here, we investigated the negative effect of a moderate dose of alcohol on CS across a wide range of spatial frequencies and with multiple levels of external noise and clarified the corresponding mechanisms in the context of a perceptual template model (PTM). To avoid the effect of alcohol washout, a quick contrast sensitivity function (qCSF) method was used to assess the visual performance of subjects before and 30 min after a moderate dose of alcohol intake. We found that (1) CS was significantly disrupted by acute alcohol intake; (2) alcohol-induced CS loss was dependent on spatial frequency and external noise; and (3) increased internal additive noise and an impaired perceptual template accounted for alcohol-induced CS loss. These results help us better understand the negative effect of alcohol consumption and provide guidance for driver safety studies.
Assessment of Fish Protein Hydrolysates in Juvenile Largemouth Bass (Micropterus salmoides) Diets: Effect on Growth, Intestinal Antioxidant Status, Immunity, and Microflora
Authors: Fan Ze , Wu Di , Li Jinnan , Zhang Yuanyuan , Cui Zhiying , Li Tianbi , Zheng Xianhu , Liu Hongbai , Wang Liansheng , Li Hongqin
Published: May 2022

Varying dietary inclusion levels of fish protein hydrolysates (FPH) were applied in a feeding experiment with juvenile largemouth bass (Micropterus salmoides) to assess their effects on growth, intestinal antioxidant status, immunity, and microflora. FPH were added in 4 dietary levels: 0 g/kg (control group, FPH-0), 10 g/kg (FPH-10), 30 g/kg (FPH-30), and 50 g/kg (FPH-50) dry matter, respectively substituting 0, 5.3, 16.3, and 27.3% of fish meal with dietary fish meal. Quadruplicate groups of 25 juvenile largemouth bass with initial body weight 9.51 ± 0.03 g were fed during the 56-day feeding experiment. Experimental results showed that fish fed FPH-30 obtained a significantly higher weight gain rate (WGR), specific growth rate (SGR), protein efficiency ratio (PER), and significant feed conversion rate (FCR) compared to the other three groups (P < 0.05). FPH-30 group also promoted protein synthesis and deposition, as evidenced by the higher whole-body crude protein contents, the higher expressions of GH1, IGF-1, TOR, and S6K in the liver, and SLC7A5, SLC7A8, SLC38A2, and SLC15A2 in the intestine than the other three groups. FPH-30 group could also enhance intestinal health status by increasing the activities of SOD, POD, CAT, GSH-Px, and T-AOC activities by upregulating the expressions of SOD, GSH-Px, IL1β, and TNFβ, and by reducing the MDA contents and the expressions of IL15, Caspase 3, Caspase 9, and Caspase 10 than other groups. Compared to the control group, the Actinobacteriota abundance markedly decreased in FPH treatments, while the variation tendency of the phylum Proteobacteria was opposite. The peak value of Firmicutes:Bacteroidetes ratio and the lowest of Bacteroidetes abundance were seen in largemouth bass fed FPH-30 (P < 0.05). Fish in three FPH treatments had lower abundances of opportunistic pathogens Staphylococcus and Plesiomonas than fish in the control group. In conclusion, FPH is a nutritious feed ingredient for juvenile largemouth bass, and can be added to a dietary level of 30 g/kg dry matter replacing fish meal without any negative effect on growth and feed utilization. FPH supplements could also strengthen the intestinal immune mechanisms of largemouth bass to tackle the immunodeficiency produced by fish meal replacement.
Machine Learning for the Prediction of Synchronous Organ-Specific Metastasis in Patients With Lung Cancer
Authors: Gao Huan , He Zhi-yi , Du Xing-li , Wang Zheng-gang , Xiang Li
Published: May 2022

Background

This study aimed to develop an artificial neural network (ANN) model for predicting synchronous organ-specific metastasis in lung cancer (LC) patients.

Methods

A total of 62,151 patients who diagnosed as LC without data missing between 2010 and 2015 were identified from Surveillance, Epidemiology, and End Results (SEER) program. The ANN model was trained and tested on an 75/25 split of the dataset. The receiver operating characteristic (ROC) curves, area under the curve (AUC) and sensitivity were used to evaluate and compare the ANN model with the random forest model.

Results

For distant metastasis in the whole cohort, the ANN model had metrics AUC = 0.759, accuracy = 0.669, sensitivity = 0.906, and specificity = 0.613, which was better than the random forest model. For organ-specific metastasis in the cohort with distant metastasis, the sensitivity in bone metastasis, brain metastasis and liver metastasis were 0.913, 0.906 and 0.925, respectively. The most important variable was separate tumor nodules with 100% importance. The second important variable was visceral pleural invasion for distant metastasis, while histology for organ-specific metastasis.

Conclusions

Our study developed a “two-step” ANN model for predicting synchronous organ-specific metastasis in LC patients. This ANN model may provide clinicians with more personalized clinical decisions, contribute to rationalize metastasis screening, and reduce the burden on patients and the health care system.
Preclinical Studies of a Novel Human PD-1 B-Cell Peptide Cancer Vaccine PD1-Vaxx From BALB/c Mice to Beagle Dogs and to Non-Human Primates (Cynomolgus Monkeys)
Authors: Guo Linlin , Overholser Jay , Good Anthony J. , Ede Nicholas J. , Kaumaya Pravin T. P.
Published: May 2022

Immunotherapy with monoclonal antibodies to checkpoint inhibitors against the PD-1/PD-L1 signaling pathway is a landmark achievement in cancer therapy. Some anti-PD-1 inhibitors such as nivolumab and pembrolizumab have shown clinical success, in a percentage of patients with prolonged survival rates. However, adverse effects accompany these benefits. In this case, strategies with lower toxicity and increased specificity are urgently required. Cancer vaccines have the ability to stimulate the native immune system and in particular, an engineered B-cell epitope can elicit high-affinity polyclonal antibodies with similar efficacy to PD-1 monoclonal antibodies in murine animal models. We have previously designed and synthesized a unique B-cell vaccine, PD1-Vaxx [MVF-PD-1(92-110)], and we have tested the immunogenicity and antitumor properties in CT26 colon cancer BALB/c syngeneic mice model. This manuscript provides results from comprehensive preclinical pharmacology studies encompassing primary and secondary pharmacodynamics, biodistribution, and safety studies. The results from these preclinical studies support the use of PD1-Vaxx in a first-in-human clinical trial in patients with non-small cell lung cancer (NSCLC). A phase I trial in patients with NSCLC has commenced.
Intersection Between Large Granular Lymphocyte Leukemia and Rheumatoid Arthritis
Authors: Moosic Katharine B. , Ananth Kusuma , Andrade Felipe , Feith David J. , Darrah Erika , Loughran Thomas P.
Published: May 2022

Large granular lymphocyte (LGL) leukemia, a rare hematologic malignancy, has long been associated with rheumatoid arthritis (RA), and the diseases share numerous common features. This review aims to outline the parallels and comparisons between the diseases as well as discuss the potential mechanisms for the relationship between LGL leukemia and RA. RA alone and in conjunction with LGL leukemia exhibits cytotoxic T-cell (CTL) expansions, HLA-DR4 enrichment, RA-associated autoantibodies, female bias, and unknown antigen specificity of associated T-cell expansions. Three possible mechanistic links between the pathogenesis of LGL leukemia and RA have been proposed, including LGL leukemia a) as a result of longstanding RA, b) as a consequence of RA treatment, or c) as a driver of RA. Several lines of evidence point towards LGL as a driver of RA. CTL involvement in RA pathogenesis is evidenced by citrullination and granzyme B cleavage that modifies the repertoire of self-protein antigens in target cells, particularly neutrophils, killed by the CTLs. Further investigations of the relationship between LGL leukemia and RA are warranted to better understand causal pathways and target antigens in order to improve the mechanistic understanding and to devise targeted therapeutic approaches for both disorders.
High Histone Deacetylase 2/3 Expression in Non-Functioning Pituitary Tumors
Authors: Zhao Wenxiu , Jiang Xiaobin , Weisenthal Karrin , Ma Jun , Botticelli Erin M. , Zhou Yunli , Hedley-Whyte E. Tessa , Wang Baiyao , Swearingen Brooke , Soberman Roy J. , Klibanski Anne , Zhang Xun
Published: May 2022

Epigenetic modification of chromatin is involved in non-malignant pituitary neoplasia by causing abnormal expression of tumor suppressors and oncogenes. These changes are potentially reversible, suggesting the possibility of targeting tumor cells by restoring the expression of epigenetically silenced tumor suppressors. The role of the histone deacetylase (HDAC) family in pituitary tumorigenesis is not known. We report that HDAC2 and 3, Class I HDAC members, are highly expressed in clinically non-functioning pituitary adenomas (NFPAs) compared to normal pituitary (NP) samples as determined by RT-PCR and immunohistochemical staining (IHC). Treatment of a human NFPA derived folliculostellate cell line, PDFS, with the HDAC3 inhibitor RGFP966 for 96 hours resulted in inhibition of cell proliferation by 70%. Furthermore, the combination of RGFP966 with a methyltransferase/DNMT inhibitor, 5’-aza-2’-deoxycytidine, led to the restoration of the expression of several tumor suppressor genes, including STAT1, P16, PTEN, and the large non-coding RNA tumor suppressor MEG3, in PDFS cells. Our data support the hypothesis that both histone modification and DNA methylation are involved in the pathogenesis of human NFPAs and suggest that targeting HDACs and DNA methylation can be incorporated into future therapies.
Targeting the Homologous Recombination Pathway in Cancer With a Novel Class of RAD51 Inhibitors
Authors: Gu Peng , Xue Liting , Zhao Chunyan , Li Wenjing , Jiang Zhen , Liu Aiguo , Li Tingting , Liu Lu , Decker Markus , Cheng Xiaoxuan , Yang Wenqing , Tang Renhong
Published: May 2022

Targeting DNA damage response (DDR) pathway has been proposed as an approach for amplifying tumor-specific replicative lesions. RAD51 plays a central role in the DDR process, and thus represents a promising anti-tumor target. We here report the discovery of a series of next generation RAD51 inhibitors that can prevent RAD51 foci formation. The lead compounds dramatically impaired human cancer cell growth, induced cell cycle arrest in S-phase, and resulted in elevated γH2AX. Furthermore, cancer cells became sensitized to chemotherapy and other DDR inhibitors. Dosed either as a single agent or in combination with cisplatin, the compounds significantly inhibited tumor growth in vivo. By upregulating ATR-CHK1 signaling, the RAD51 inhibitors increased surface PD-L1 levels in various tumor cells, suggesting a potential combination of RAD51 inhibitors with PD-1/PD-L1 blockade. Overall, our findings provide the preclinical rationale to explore RAD51 inhibitors as monotherapy or in combination with chemotherapy, immunotherapy or DDR-targeting therapy in cancer treatment.
A Novel Karyoplasmic Ratio-Based Automatic Recognition Method for Identifying Glioma Circulating Tumor Cells
Authors: Zhu Xinyi , Wen Shen , Deng Shuhang , Wu Gao , Tian Ruyong , Hu Ping , Ye Liguo , Sun Qian , Xu Yang , Deng Gang , Zhang Dong , Yang Shuang , Qi Yangzhi , Chen Qianxue
Published: May 2022

Background

Detection of circulating tumor cells (CTCs) is a promising technology in tumor management; however, the slow development of CTC identification methods hinders their clinical utility. Moreover, CTC detection is currently challenging owing to major issues such as isolation and correct identification. To improve the identification efficiency of glioma CTCs, we developed a karyoplasmic ratio (KR)-based identification method and constructed an automatic recognition algorithm. We also intended to determine the correlation between high-KR CTC and patients’ clinical characteristics.

Methods

CTCs were isolated from the peripheral blood samples of 68 glioma patients and analyzed using DNA-seq and immunofluorescence staining. Subsequently, the clinical information of both glioma patients and matched individuals was collected for analyses. ROC curve was performed to evaluate the efficiency of the KR-based identification method. Finally, CTC images were captured and used for developing a CTC recognition algorithm.

Results

KR was a better parameter than cell size for identifying glioma CTCs. We demonstrated that low CTC counts were independently associated with isocitrate dehydrogenase (IDH) mutations (p = 0.024) and 1p19q co-deletion status (p = 0.05), highlighting its utility in predicting oligodendroglioma (area under the curve = 0.770). The accuracy, sensitivity, and specificity of our algorithm were 93.4%, 81.0%, and 97.4%, respectively, whereas the precision and F1 score were 90.9% and 85.7%, respectively.

Conclusion

Our findings remarkably increased the efficiency of detecting glioma CTCs and revealed a correlation between CTC counts and patients’ clinical characteristics. This will allow researchers to further investigate the clinical utility of CTCs. Moreover, our automatic recognition algorithm can maintain high precision in the CTC identification process, shorten the time and cost, and significantly reduce the burden on clinicians.
Metformin Regulates Alveolar Macrophage Polarization to Protect Against Acute Lung Injury in Rats Caused by Paraquat Poisoning
Authors: Yuan Ding , Li Yi , Hou Linlin , Yang Fang , Meng Cuicui , Yu Yanwu , Sun Changhua , Duan Guoyu , Xu Zhigao , Zhu Guiying , Guo Jianjun , Zhang Leilei , Yan Gaiqin , Chen Jihong , Yang Yanan , Zhang Yan , Gao Yanxia
Published: May 2022

This study explored the role of metformin (MET) in regulating the polarization of alveolar macrophages to protect against acute lung injury (ALI) in rats caused by paraquat (PQ) poisoning. The in vivo studies showed that the 35 mg/kg dose of MET increased the survival rate of rats, alleviated pathological damages to the lungs and their systemic inflammation, promoted the reduction of the pro-inflammatory factors interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels, and increased the anti-inflammatory factor IL-10 levels in the rat serum. At the same time, the MET intervention decreased the expression of M1 macrophage marker iNOS in the lungs of the PQ-poisoned rats while increasing the M2 macrophage marker, Arg1, expression. In vitro, the concentration of MET > 10 mmol/L affected NR8383 viability adversely and was concentration-dependent; however, no adverse impact on NR8383 viability was observed at MET ≤ 10 mmol/L concentration, resisting the reducing effect of PQ on NR8383 vitality. The PQ-induced NR8383 model with MET intervention showed significantly reduced secretions of IL-6 and TNF-α in NR8383, and lowered expressions of M1 macrophage markers iNOS and CD86. Additionally, MET increased IL-10 secretion and the M2 macrophage markers, Arg1 and Mrcl, expressions. Therefore, we speculate that MET could regulate alveolar macrophage polarization to protect against PQ-poisoning caused ALI.
Survival Benefit of Metformin as an Adjuvant Treatment for Head and Neck Cancer: A Systematic Review and Meta-Analysis
Authors: Jiao Yu , Liu Dongjuan , Sun Yi , Chen Zitong , Liu Sai
Published: May 2022

Background/Aims: The relationship between the efficacy of metformin and the prognosis of patients with head and neck cancer (HNC) was still unclear. This study aims to clarify the prognostic value of metformin treatment using meta-analysis.

Methods: Studies related to HNC prognosis and metformin were searched in Cochrane Library, Embase, LILACS, MEDLINE and PubMed databases. A meta-analysis was performed to evaluate the association between metformin therapy and the prognosis of HNC on overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS) and whether article quality, comorbidities, age, region or smoking had an influence on the prognosis of metformin treatment. Pooled hazard ratio (HR) and 95% confidence interval (CI) were analyzed to assess the effect.

Results: Eleven eligible studies involving 14,694 participants were included. Metformin increased the OS (HR = 0.87, 95% CI: 0.76–0.99), but failed on DFS (HR = 0.67, 95% CI: 0.40–1.09) or DSS (HR = 0.69, 95% CI: 0.41–1.14) in HNC patients. Subgroup analysis showed metformin was associated with improved OS (HR = 0.66, 95% CI: 0.49–0.88), DFS (HR = 0.49, 95% CI: 0.26–0.92) and DSS (HR = 0.38, 95% CI: 0.22–0.65) in studies with higher Newcastle-Ottawa Scale (NOS) scores. Subgroup analysis of age indicated that patients younger than 65 years (OS, HR = 0.67, 95% CI: 0.49–0.92) were more likely to benefit from metformin treatment. Subgroup analysis of comorbidities showed metformin significantly improved patient outcomes in studies without adjusted for comorbidities (OS, HR = 0.66, 95% CI: 0.51–0.85; DSS, HR = 0.38, 95% CI: 0.22–0.65), but not in studies that adjusted for comorbidities.

Conclusions: Metformin improved the prognosis of HNC patients as an adjuvant therapy, especially in those with higher NOS scores. Age and comorbidities of HNC patients influenced the therapeutic effect of metformin. Further well-conducted investigations are needed.
Dapagliflozin Attenuates Myocardial Fibrosis by Inhibiting the TGF-β1/Smad Signaling Pathway in a Normoglycemic Rabbit Model of Chronic Heart Failure
Authors: Chen Xuefeng , Yang Qian , Bai Wenlou , Yao Wenjing , Liu Litian , Xing Yuanyuan , Meng Cunliang , Qi Peng , Dang Yi , Qi Xiaoyong
Published: May 2022

Recent studies have shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors play a beneficial role for normoglycemic patients with heart failure (HF). However, the underlying mechanism remains largely unexplored. In the present study, we aimed to investigate the cardioprotective effect of SGLT2 inhibitors in a normoglycemic rabbit model of chronic heart failure (CHF) and its potential mechanism was also explored. A total of 24 male New Zealand white rabbits were randomly divided into the sham group, HF group, perindopril group, and dapagliflozin (DAPA) group. The normoglycemic CHF model was established by aortic constriction for 12 weeks. In the 13th week, DAPA (1 mg/kg/day) or perindopril (0.5 mg/kg/day) was administered by oral gavage daily for 10 weeks. Both the sham group and HF group were given normal saline via gavage. After 10 weeks, the heart structure and function were evaluated by echocardiography and plasma NT-proBNP. Moreover, cardiac fibrosis was analyzed using immunohistochemistry, Masson’s trichrome staining, and Western blotting analysis. The results showed that DAPA improved the myocardial structure and function of normoglycemic CHF rabbits and ameliorated myocardial fibrosis. Further study indicated that DAPA suppressed cardiac fibrosis by inhibiting the transforming growth factor β1 (TGF-β1)/Smad signaling pathway. Collectively, our findings showed that DAPA could ameliorate cardiac fibrosis in normoglycemic CHF rabbits by inhibiting the TGF-β1/Smad signaling pathway.
Mannose: A Sweet Option in the Treatment of Cancer and Inflammation
Authors: Nan Fang , Sun Yutong , Liang Hantian , Zhou Jingyang , Ma Xiao , Zhang Dunfang
Published: May 2022

As a natural sugar, mannose is a type of hexose that is abundant in many different types of fruits. Since mannose is rarely used for glycolysis in mammals, studies on the role of mannose have not attracted much attention. Glycosylation of specific proteins was thought to be the major function of mannose. Surprisingly, during the past few years, mannose was found to be effective in promoting immune tolerance and suppressing inflammatory diseases related to autoimmunity and allergy. Moreover importantly, mannose was also found to be efficient in suppressing tumors by suppressing glycolysis and enhancing chemotherapeutic agents. In this review, we summarize the recent studies of mannose on antitumor properties and anti-inflammatory characteristics. We emphasize that mannose could play a beneficial role in the treatment of a variety of diseases, including cancers and inflammatory diseases, and could be a novel therapeutic strategy that deserves continued evaluation.
Treatment-Related Coronary Disorders of Fluoropyrimidine Administration: A Systematic Review and Meta-Analysis
Authors: Lu Yajie , Deng Shizhou , Dou Qiongyi , Pan Wei , Liu Qingqing , Ji Hongchen , Wang Xiaowen , Zhang Hong-Mei
Published: May 2022

Background: Coronary disorders are recognized as the most common manifestation of fluoropyrimidine-related cardiotoxicity in clinical practice. However, there are limited and conflicting data on the incidence and profiles of fluoropyrimidine-related coronary disorders. In this meta-analysis, we aimed to systematically assess the incidence of all-grade and grade 3 or higher fluoropyrimidine-related coronary disorders, and further explore the factors that influence its occurrence.

Methods: Studies reporting the fluoropyrimidine-related coronary disorders were retrieved from a systematic search of English literature in the PubMed, Web of Science, Medline, and Cochrane database from 1 Jan 2001, to 1 Jan 2022. The NIH assessment tool was used to evaluate the quality of each study. The data of basic study characteristics, treatment details, and results of coronary toxicities were extracted. According to the results of the heterogeneity test (I2 and p-value statistic), a random-effect model or fixed-effect model was selected for the pooled analysis of the incidence of adverse coronary events. Subgroup analysis was conducted to further explore the risks influencing the occurrence of fluoropyrimidine-related coronary disorders. The stability and publication bias of our results were evaluated by sensitivity analysis and Egger test, respectively.

Results: A total of 63 studies were finally included in our pooled analysis, involving 25,577 patients. The pooled cumulative incidence of all-grade and grade 3 or higher coronary disorders was 2.75% (95% CI 1.89%–3.76%) and 1.00% (95% CI 0.62%–1.47%), respectively. The coronary disorders were most reported as myocardial ischemia (1.28%, 95% CI 0.42%–2.49%) and angina/chest pain (1.1%, 95% CI 0.54%–1.81%). Subgroup analysis revealed that studies in the female-only population seemed to have a lower incidence of fluoropyrimidine-related coronary disorders. The occurrence of adverse coronary events varied among different tumor types. Patients with esophageal cancer have the highest coronary toxicity (6.32%), while those with breast cancer have a relatively lower incidence (0.5%). Coronary disorders induced by 5-FU monotherapy are more frequent than that induced by capecitabine (3.31% vs. 1.21%, p < 0.01). Fluoropyrimidine combination therapy, whether combined with other chemotherapy drugs, targeted therapy drugs, or radiotherapy, significantly increased the incidence of coronary complications (p < 0.01).

Conclusion: This meta-analysis has defined the incidence of fluoropyrimidine-related coronary disorders and depicted its epidemiological profiles for the first time, which may provide a reference for clinical practice in cancer management.
FUN14 Domain Containing 1 (FUNDC1): A Promising Mitophagy Receptor Regulating Mitochondrial Homeostasis in Cardiovascular Diseases
Authors: Mao Yu , Ren Jun , Yang Lifang
Published: May 2022

Mitochondria, the intracellular organelles for cellular aerobic respiration and energy production, play an important role in the regulation of cell metabolism and cell fate. Mitophagy, a selective form of autophagy, maintains dynamic homeostasis of cells through targeting long-lived or defective mitochondria for timely clearance and recycling. Dysfunction in mitophagy is involved in the molecular mechanism responsible for the onset and development of human diseases. FUN14 domain containing 1 (FUNDC1) is a mitochondrial receptor located in the outer mitochondria membrane (OMM) to govern mitophagy process. Emerging evidence has demonstrated that levels and phosphorylation states of FUNDC1 are closely related to the occurrence, progression and prognosis of cardiovascular diseases, indicating a novel role for this mitophagy receptor in the regulation of mitochondrial homeostasis in cardiovascular system. Here we review mitophagy mediated by FUNDC1 in mitochondria and its role in various forms of cardiovascular diseases.
Metformin Ameliorates Chronic Colitis-Related Intestinal Fibrosis via Inhibiting TGF-β1/Smad3 Signaling
Authors: Wang Ying , Wang Zhi , Yang Huiping , Chen Shuze , Zheng Dekai , Liu Xiuying , Jiang Qinrui , Chen Ye
Published: May 2022

Intestinal fibrosis is considered to be a chronic complication of inflammatory bowel disease (IBD) and seriously threatening human health. Effective medical therapies or preventive measures are desirable but currently unavailable. Metformin has been proved to have a satisfactory anti-inflammatory effects in ulcerative colitis (UC) patients. Whether metformin can ameliorate chronic colitis-related intestinal fibrosis and the possible mechanisms remain unclear. Here, we established colitis-related intestinal fibrosis in mice by repetitive administration of TNBS or DSS. Preventive and therapeutic administration of metformin to chronic TNBS or DSS colitis mice indicated that metformin significantly attenuated intestinal fibrosis by suppressing Smad3 phosphorylation. In vitro studies with human colon fibroblast cell line (CCD-18Co) and primary human intestinal fibroblast treated with TGF-β1 confirmed the anti-fibrotic function of metformin for fibroblast activation, proliferation and collagen production. Mechanistically, metformin particularly inhibited phosphorylation and nuclear translocation of Smad3 by blocking the interaction of Smad3 with TβRI. These findings suggest that metformin will be an attractive anti-fibrotic drug for intestinal fibrosis in future therapies.
Therapeutic Effects of Natural Products on Cervical Cancer: Based on Inflammatory Pathways
Authors: Zhou Zi-Wei , Long Hui-Zhi , Xu Shuo-Guo , Li Feng-Jiao , Cheng Yan , Luo Hong-Yu , Gao Li-Chen
Published: May 2022

Inflammation is a protective response of the body to an irritant. When an inflammatory response occurs, immune cells are recruited to the injury, eliminating the irritation. The excessive inflammatory response can cause harm to the organism. Inflammation has been found to contribute to cervical cancer if there is a problem with the regulation of inflammatory response. Cervical cancer is one of the most common malignant tumors globally, and the incidence tends to be younger. The harm of cervical cancer cannot be ignored. The standard treatments for cervical cancer include surgery, radiotherapy and chemotherapy. However, the prognosis for this treatment is poor, so it is urgent to find a safer and more effective treatment. Natural products are considered excellent candidates for the treatment of cervical cancer. In this review, we first describe the mechanisms by which inflammation induces cervical cancer. Subsequently, we highlight natural products that can treat cervical cancer through inflammatory pathways. We also introduce natural products for the treatment of cervical cancer in clinical trials. Finally, methods to improve the anticancer properties of natural products were added, and the development status of natural products was discussed.
Omics Technology for the Promotion of Nutraceuticals and Functional Foods
Authors: Pandita Deepu , Pandita Anu
Published: May 2022

The influence of nutrition and environment on human health has been known for ages. Phytonutrients (7,000 flavonoids and phenolic compounds; 600 carotenoids) and pro-health nutrients—nutraceuticals positively add to human health and may prevent disorders such as cancer, diabetes, obesity, cardiovascular diseases, and dementia. Plant-derived bioactive metabolites have acquired an imperative function in human diet and nutrition. Natural phytochemicals affect genome expression (nutrigenomics and transcriptomics) and signaling pathways and act as epigenetic modulators of the epigenome (nutri epigenomics). Transcriptomics, proteomics, epigenomics, miRNomics, and metabolomics are some of the main platforms of complete omics analyses, finding use in functional food and nutraceuticals. Now the recent advancement in the integrated omics approach, which is an amalgamation of multiple omics platforms, is practiced comprehensively to comprehend food functionality in food science.
Spaceflight-Associated Vascular Remodeling and Gene Expression in Mouse Calvaria
Authors: Siamwala Jamila H. , Macias Brandon R. , Healey Robert , Bennett Brett , Hargens Alan R.
Published: May 2022

Astronauts suffer from a loss of bone mass at a rate of 1.5% per month from lower regions of the body during the course of long-duration (>30 days) spaceflight, a phenomenon that poses important risks for returning crew. Conversely, a gain in bone mass may occur in non-load bearing regions of the body as related to microgravity-induced cephalad fluid shift. Representing non-load bearing regions with mouse calvaria and leveraging the STS-131 (15-day) and BION-M1 (30-day) flights, we examined spatial and temporal calvarial vascular remodeling and gene expression related to microgravity exposure compared between spaceflight (SF) and ground control (GC) cohorts. We examined parasagittal capillary numbers and structures in calvaria from 16 to 23 week-old C57BL/6 female mice (GC, n = 4; SF, n = 5) from STS-131 and 19–20 week-old C57BL/6 male mice (GC, n = 6; SF, n = 6) from BION-M1 using a robust isolectin-IB4 vessel marker. We found that the vessel diameter reduces significantly in mice exposed to 15 days of spaceflight relative to control. Capillarization increases by 30% (SF vs. GC, p = 0.054) in SF mice compared to GC mice. The vessel numbers and diameter remain unchanged in BION-M1 mice calvarial section. We next analyzed the parietal pro-angiogenic (VEGFA) and pro-osteogenic gene (BMP-2, DMP1, RUNX2 and OCN) expression in BION-M1 mice using quantitative RT-PCR. VEGFA gene expression increased 15-fold while BMP-2 gene expression increased 11-fold in flight mice compared to GC. The linkage between vascular morphology and gene expression in the SF conditions suggests that angiogenesis may be important in the regulation of pathological bone growth in non-weight bearing regions of the body. Short-duration microgravity-mediated bone restructuring has implications in planning effective countermeasures for long-duration flights and extraterrestrial human habitation.
Emerging Roles of Plant DNA-Binding With One Finger Transcription Factors in Various Hormone and Stress Signaling Pathways
Authors: Wang Zemin , Wong Darren Chern Jan , Chen Zhengliang , Bai Wei , Si Huaijun , Jin Xin
Published: May 2022

Coordinated transcriptional regulation of stress-responsive genes orchestrated by a complex network of transcription factors (TFs) and the reprogramming of metabolism ensure a plant’s continued growth and survival under adverse environmental conditions (e.g., abiotic stress). DNA-binding with one finger (Dof) proteins, a group of plant-specific TF, were identified as one of several key components of the transcriptional regulatory network involved in abiotic stress responses. In many plant species, Dofs are often activated in response to a wide range of adverse environmental conditions. Dofs play central roles in stress tolerance by regulating the expression of stress-responsive genes via the DOFCORE element or by interacting with other regulatory proteins. Moreover, Dofs act as a key regulatory hub of several phytohormone pathways, integrating abscisic acid, jasmonate, SA and redox signaling in response to many abiotic stresses. Taken together, we highlight a unique role of Dofs in hormone and stress signaling that integrates plant response to adverse environmental conditions with different aspects of plant growth and development.
Origin, Expansion, and Divergence of ETHYLENE-INSENSITIVE 3 (EIN3)/EIN3-LIKE Transcription Factors During Streptophytes Evolution
Authors: Mao Kexin , Zhang Minghui , Kong Yadong , Dai Shanshan , Wang Yong , Meng Qingwei , Ma Nana , Lv Wei
Published: May 2022

The transition of plants to land required several regulatory adaptive mechanisms. Little is known about these mechanisms, but they no doubt involved the evolution of transcription factor (TF) families. ETHYLENE-INSENSITIVE 3 (EIN3)/EIN3-LIKE (EIL) transcription factors (TFs) are core components of the ethylene signaling pathway that play important roles in almost every aspect of plant development and environmental responses by regulating the transcription of numerous genes. However, the evolutionary history of EIN3/EIL TFs, which are present in a wide range of streptophytes, is still not clear. Here, to explore the evolution and functions of EIN3/EIL TFs, we performed phylogenetic analysis of these TFs and investigated their gene and protein structures as well as sequence features. Our results suggest that the EIN3/EIL TF family was already was already present in the ancestor of streptophyte algae. Phylogenetic analysis divided the EIN3/EIL TFs into three groups (Group A–C). Analysis of gene and protein structure revealed that most of the structural features of these TFs had already formed in ancient lineages. Further investigation suggested that all groups have undergone several duplication events related to whole-genome duplications in plants, generating multiple, functionally diverse gene copies. Therefore, as plants colonized terrestrial habitats and evolved key traits, the EIN3/EIL TF family expanded broadly via multiple duplication events, which could have promoted their fundamental neo- and sub-functionalization to help plants adapt to terrestrial life. Our findings shed light on the functional evolution of the EIN3/EIL TF family in the streptophytes.
Cotton Breeding in Australia: Meeting the Challenges of the 21st Century
Authors: Conaty Warren C. , Broughton Katrina J. , Egan Lucy M. , Li Xiaoqing , Li Zitong , Liu Shiming , Llewellyn Danny J. , MacMillan Colleen P. , Moncuquet Philippe , Rolland Vivien , Ross Brett , Sargent Demi , Zhu Qian-Hao , Pettolino Filomena A. , Stiller Warwick N.
Published: May 2022

The Commonwealth Scientific and Industrial Research Organisation (CSIRO) cotton breeding program is the sole breeding effort for cotton in Australia, developing high performing cultivars for the local industry which is worth∼AU$3 billion per annum. The program is supported by Cotton Breeding Australia, a Joint Venture between CSIRO and the program’s commercial partner, Cotton Seed Distributors Ltd. (CSD). While the Australian industry is the focus, CSIRO cultivars have global impact in North America, South America, and Europe. The program is unique compared with many other public and commercial breeding programs because it focuses on diverse and integrated research with commercial outcomes. It represents the full research pipeline, supporting extensive long-term fundamental molecular research; native and genetically modified (GM) trait development; germplasm enhancement focused on yield and fiber quality improvements; integration of third-party GM traits; all culminating in the release of new commercial cultivars. This review presents evidence of past breeding successes and outlines current breeding efforts, in the areas of yield and fiber quality improvement, as well as the development of germplasm that is resistant to pests, diseases and abiotic stressors. The success of the program is based on the development of superior germplasm largely through field phenotyping, together with strong commercial partnerships with CSD and Bayer CropScience. These relationships assist in having a shared focus and ensuring commercial impact is maintained, while also providing access to markets, traits, and technology. The historical successes, current foci and future requirements of the CSIRO cotton breeding program have been used to develop a framework designed to augment our breeding system for the future. This will focus on utilizing emerging technologies from the genome to phenome, as well as a panomics approach with data management and integration to develop, test and incorporate new technologies into a breeding program. In addition to streamlining the breeding pipeline for increased genetic gain, this technology will increase the speed of trait and marker identification for use in genome editing, genomic selection and molecular assisted breeding, ultimately producing novel germplasm that will meet the coming challenges of the 21st Century.
Successful Production and Ligninolytic Activity of a Bacterial Laccase, Lac51, Made in Nicotiana benthamiana via Transient Expression
Authors: van Eerde André , Várnai Anikó , Wang Yanliang , Paruch Lisa , Jameson John-Kristian , Qiao Fen , Eiken Hans Geir , Su Hang , Eijsink Vincent G. H. , Clarke Jihong Liu
Published: May 2022

Giant panda could have bamboo as their exclusive diet for about 2 million years because of the contribution of numerous enzymes produced by their gut bacteria, for instance laccases. Laccases are blue multi-copper oxidases that catalyze the oxidation of a broad spectrum of phenolic and aromatic compounds with water as the only byproduct. As a “green enzyme,” laccases have potential in industrial applications, for example, when dealing with degradation of recalcitrant biopolymers, such as lignin. In the current study, a bacterial laccase, Lac51, originating from Pseudomonas putida and identified in the gut microbiome of the giant panda’s gut was transiently expressed in the non-food plant Nicotiana benthamiana and characterized. Our results show that recombinant Lac51 exhibits bacterial laccase properties, with optimal pH and temperature at 7–8 and 40°C, respectively, when using syringaldazine as substrate. Moreover, we demonstrate the functional capability of the plant expressed Lac51 to oxidize lignin using selected lignin monomers that serve as substrates of Lac51. In summary, our study demonstrates the potential of green and non-food plants as a viable enzyme production platform for bacterial laccases. This result enriches our understanding of plant-made enzymes, as, to our knowledge, Lac51 is the first functional recombinant laccase produced in plants.