bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Repetitive Transcranial Magnetic Stimulation of Cerebellar Swallowing Cortex on Brain Neural Activities: A Resting-State fMRI Study
Authors: Dong Linghui , Ma Wenshuai , Wang Qiang , Pan Xiaona , Wang Yuyang , Han Chao , Meng Pingping
Published: April 2022

Objective

The effects and possible mechanisms of cerebellar high-frequency repetitive transcranial magnetic stimulation (rTMS) on swallowing-related neural networks were studied using resting-state functional magnetic resonance imaging (rs-fMRI).

Method

A total of 23 healthy volunteers were recruited, and 19 healthy volunteers were finally included for the statistical analysis. Before stimulation, the cerebellar hemisphere dominant for swallowing was determined by the single-pulse TMS. The cerebellar representation of the suprahyoid muscles of this hemisphere was selected as the target for stimulation with 10 Hz rTMS, 100% resting motor threshold (rMT), and 250 pulses, with every 1 s of stimulation followed by an interval of 9 s. The motor evoked potential (MEP) amplitude of the suprahyoid muscles in the bilateral cerebral cortex was measured before and after stimulation to evaluate the cortical excitability. Forty-eight hours after elution, rTMS was reapplied on the dominant cerebellar representation of the suprahyoid muscles with the same stimulation parameters. Rs-fMRI was performed before and after stimulation to observe the changes in amplitude of low-frequency fluctuation (ALFF) and regional homology (ReHo) at 0.01–0.08 Hz, 0.01–0.027 Hz, and 0.027–0.073 Hz.

Results

After cerebellar high-frequency rTMS, MEP recorded from swallowing-related bilateral cerebral cortex was increased. The results of rs-fMRI showed that at 0.01–0.08 Hz, ALFF was increased at the pons, right cerebellum, and medulla and decreased at the left temporal lobe, and ReHo was decreased at the left insular lobe, right temporal lobe, and corpus callosum. At 0.01–0.027 Hz, ALFF was decreased at the left temporal lobe, and ReHo was decreased at the right temporal lobe, left putamen, and left supplementary motor area.

Conclusion

Repetitive transcranial magnetic stimulation of the swallowing cortex in the dominant cerebellar hemisphere increased the bilateral cerebral swallowing cortex excitability and enhanced pontine, bulbar, and cerebellar spontaneous neural activity, suggesting that unilateral high-frequency stimulation of the cerebellum can excite both brainstem and cortical swallowing centers. These findings all provide favorable support for the application of cerebellar rTMS in the clinical practice.
Optical Coherence Tomography Evaluation of Carotid Artery Stenosis and Stenting in Patients With Previous Cervical Radiotherapy
Authors: Xu Xiaohui , Huang Feihong , Shi Xuan , Liu Rui , Han Yunfei , Li Min , Wang Fang , Yang Qingwen , Zhu Wusheng , Ye Ruidong , Liu Xinfeng
Published: April 2022

Objectives

Cervical radiotherapy can lead to accelerated carotid artery stenosis, increased incidence of stroke, and a higher rate of in-stent restenosis in irradiated patients. Our objective was to reveal the morphological characteristics of radiation-induced carotid stenosis (RICS) and the stent–vessel interactions in patients with previous cervical radiotherapy by optical coherence tomography (OCT).

Materials and Methods

Between November 2017 and March 2019, five patients with a history of cervical radiotherapy were diagnosed with severe carotid artery stenosis and underwent carotid artery stenting (CAS). OCT was conducted before and immediately after the carotid stent implantation. Two patients received OCT evaluation of carotid stenting at 6- or 13-month follow-up.

Results

The tumor types indicating cervical radiotherapy were nasopharyngeal carcinoma (n = 3), cervical esophageal carcinoma (n = 1), and cervical lymphoma (n = 1). The median interval from the radiotherapy to the diagnosis of RICS was 8 years (range 4–36 years). Lesion characteristics of RICS were detected with heterogeneous signal-rich tissue, dissection, and advanced atherosclerosis upon OCT evaluation. Post-interventional OCT revealed 18.2–57.1% tissue protrusion and 3.3–13.8% stent strut malapposition. Follow-up OCT detected homogeneous signal-rich neointima and signal-poor regions around stent struts. In the patient with high rates of tissue protrusion and stent strut malapposition, the 6-month neointima burden reached 48.9% and microvessels were detected.

Conclusion

The morphological features of RICS were heterogeneous, including heterogeneous signal-rich tissue, dissection, and advanced atherosclerosis. Stenting was successful in all 5 patients with severe RICS. One patient, with high rates of tissue protrusion and stent strut malapposition immediately after stenting, received in-stent neointimal hyperplasia at a 6-month follow-up.
Supporting Cells and Their Potential Roles in Cisplatin-Induced Ototoxicity
Authors: Waissbluth Sofia , Maass Juan Cristóbal , Sanchez Helmuth A. , Martínez Agustín D.
Published: April 2022

Cisplatin is a known ototoxic chemotherapy drug, causing irreversible hearing loss. Evidence has shown that cisplatin causes inner ear damage as a result of adduct formation, a proinflammatory environment and the generation of reactive oxygen species within the inner ear. The main cochlear targets for cisplatin are commonly known to be the outer hair cells, the stria vascularis and the spiral ganglion neurons. Further evidence has shown that certain transporters can mediate cisplatin influx into the inner ear cells including organic cation transporter 2 (OCT2) and the copper transporter Ctr1. However, the expression profiles for these transporters within inner ear cells are not consistent in the literature, and expression of OCT2 and Ctr1 has also been observed in supporting cells. Organ of Corti supporting cells are essential for hair cell activity and survival. Special interest has been devoted to gap junction expression by these cells as certain mutations have been linked to hearing loss. Interestingly, cisplatin appears to affect connexin expression in the inner ear. While investigations regarding cisplatin-induced hearing loss have been focused mainly on the known targets previously mentioned, the role of supporting cells for cisplatin-induced ototoxicity has been overlooked. In this mini review, we discuss the implications of supporting cells expressing OCT2 and Ctr1 as well as the potential role of gap junctions in cisplatin-induced cytotoxicity.
Estimating High-Order Brain Functional Networks in Bayesian View for Autism Spectrum Disorder Identification
Authors: Jiang Xiao , Zhou Yueying , Zhang Yining , Zhang Limei , Qiao Lishan , De Leone Renato
Published: April 2022

Brain functional network (BFN) has become an increasingly important tool to understand the inherent organization of the brain and explore informative biomarkers of neurological disorders. Pearson’s correlation (PC) is the most widely accepted method for constructing BFNs and provides a basis for designing new BFN estimation schemes. Particularly, a recent study proposes to use two sequential PC operations, namely, correlation’s correlation (CC), for constructing the high-order BFN. Despite its empirical effectiveness in identifying neurological disorders and detecting subtle changes of connections in different subject groups, CC is defined intuitively without a solid and sustainable theoretical foundation. For understanding CC more rigorously and providing a systematic BFN learning framework, in this paper, we reformulate it in the Bayesian view with a prior of matrix-variate normal distribution. As a result, we obtain a probabilistic explanation of CC. In addition, we develop a Bayesian high-order method (BHM) to automatically and simultaneously estimate the high- and low-order BFN based on the probabilistic framework. An efficient optimization algorithm is also proposed. Finally, we evaluate BHM in identifying subjects with autism spectrum disorder (ASD) from typical controls based on the estimated BFNs. Experimental results suggest that the automatically learned high- and low-order BFNs yield a superior performance over the artificially defined BFNs via conventional CC and PC.
Changes in Brain Neuroimmunology Following Injury and Disease
Authors: Tabet Anthony , Apra Caroline , Stranahan Alexis M. , Anikeeva Polina
Published: April 2022

The nervous and immune systems are intimately related in the brain and in the periphery, where changes to one affect the other and vice-versa. Immune cells are responsible for sculpting and pruning neuronal synapses, and play key roles in neuro-development and neurological disease pathology. The immune composition of the brain is tightly regulated from the periphery through the blood-brain barrier (BBB), whose maintenance is driven to a significant extent by extracellular matrix (ECM) components. After a brain insult, the BBB can become disrupted and the composition of the ECM can change. These changes, and the resulting immune infiltration, can have detrimental effects on neurophysiology and are the hallmarks of several diseases. In this review, we discuss some processes that may occur after insult, and potential consequences to brain neuroimmunology and disease progression. We then highlight future research directions and opportunities for further tool development to probe the neuro-immune interface.
Associations Between Dietary Patterns and Neuroimaging Markers: A Systematic Review
Authors: Townsend Rebecca F. , Woodside Jayne V. , Prinelli Federica , O’Neill Roisin F. , McEvoy Claire T.
Published: April 2022

Dementia is a complex, growing challenge for population health worldwide. Dietary patterns (DPs) may offer an opportunity to beneficially influence cognitive ageing and potentially reduce an individuals’ risk of dementia through diet-related mechanisms. However, previous studies within this area have shown mixed results, which may be partly explained by the lack of sensitivity and accuracy within cognitive testing methods. Novel neuroimaging techniques provide a sensitive method to analyse brain changes preceding cognitive impairment which may have previously remained undetected. The purpose of this systematic review was to elucidate the role of DPs in relation to brain ageing processes, by summarising current prospective and intervention studies. Nine prospective studies met the inclusion criteria for the review, seven evaluated the Mediterranean diet (MeDi), one evaluated the Alternative Healthy Eating Index-2010, and one evaluated a posteriori derived DPs. No intervention studies were eligible for inclusion in this review. There was some evidence of an association between healthy DPs and neuroimaging markers including changes within these markers over time. Consequently, it is plausible that better adherence to such DPs may positively influence brain ageing and neurodegeneration. Future studies may benefit from the use of multi-modal neuroimaging techniques, to further investigate how adherence to a DP influences brain health. The review also highlights the crucial need for further intervention studies within this research area.
Integrating Effects of Human Physiology, Psychology, and Individual Variations on Satiety–An Exploratory Study
Authors: Ni Dongdong , Smyth Heather E. , Cozzolino Daniel , Gidley Michael J.
Published: April 2022

Satiety can influence food intake, and as a consequence has the potential to affect weight and obesity. Human factors such as physiology and psychology are likely to be important in determining satiety. However, it is not well-understood how these factors (individual variations) alone or combined contribute to satiety feelings. In addition, there have been limited or no attempts to use a holistic approach to evaluate satiety. In this study, three plant-based foods were used as mid-morning snack for 52 participants to evaluate satiety response (during three consecutive days, one-day-one-food type). The foods were served ad libitum until participants felt comfortably full prior to satiety monitoring. The study explored diverse human factors (n = 30) that might contribute to satiety including those related to oral physiology, metabolic factors, body composition and psychology. It identified important variables for satiety as well as the interactions among them and the influences of age, gender, and low satiety phenotype (consistently lower reported fullness scores) on satiety. Overall, combinations of factors rather than individual ones contributed to self-reported satiety. Food factors (e.g., type, composition) had limited effects, but there were only three types used in the study. The combination of metabolic factors [respiratory quotient, age, and body energy usage type (e.g., carbohydrate or fat)], oral sensitivity & processing, personality traits (agreeableness, conscientiousness, and neuroticism), and eating behavior (e.g., emotional and external eating) were the most important for explaining individual satiety responses. Older participants had significantly higher reported satiety than younger participants, associated with significant differences in oral physiology, increased body fat, and mature psychological characters. Moreover, different satiety phenotypes had significant differences in relationships with body fat, oral physiology, personalities, food neophobia, and eating behaviors. The results of this study indicate that much greater insights into the factors determining satiety responses can be obtained by combining multiple food and human physiological and psychological characteristics. This study used more diverse measures of individual variation than previous studies of satiety and points the way toward a more holistic approach to understanding the (control of) perceptions of fullness at both individual and group levels.
Plant-Based: A Perspective on Nutritional and Technological Issues. Are We Ready for “Precision Processing”?
Authors: Menta Roberto , Rosso Ginevra , Canzoneri Federico
Published: April 2022

The rapid evolution of consumers' preference despite being still rooted in taste is rapidly combining with an exponential growth of environmental awareness. Both are forcing innovation into the food industry sector. Today, it is common in the scientific literature to find awareness of nutrition and sustainability, functionality and freshness, taste, and pollution; the most relevant and recognized trends are evolving with unprecedent speed toward a new paradigm. The perfect storm of fast-growing population, together with an exploding level of environmental pollution, is combining with the request for functional foods with more defined health properties and is strongly pushing the food sector to new defined innovation objectives to keep and develop the economic role of most loved brands around the world. The most debated conundrum is how to provide healthy food for all human beings, without further affecting our Mother Earth. Innovation in food raw materials as well as innovation in food processing seems to be the magic solution to provide twice with half, that is, to double the food production combined with declining resources. One of the fastest growing segments in the food industry is the plant-based segment. The status of the available options in food processing applied to plant-based food will be discussed, with a special focus on novel physical processing technologies and atomic force microscopy as possible complementary weapons in science-based definition of a sustainable nutrition approach. A call for a new paradigm such as “precision processing” should be adopted to drive the evolution of the whole food system.
Effect of Fermentation Time on Molecular Structure and Physicochemical Properties of Corn Ballast Starch
Authors: Wei Chunhong , Ge Yunfei , Zhao Shuting , Liu Dezhi , Jiliu Junlan , Wu Yunjiao , Hu Xin , Wei Mingzhi , Wang Yifei , Wang Weihao , Wang Lidong , Cao LongKui
Published: April 2022

The effect of fermentation treatment on the surface morphology, crystal structure, molecular weight, chain length distribution, and physicochemical properties of corn starch was investigated using natural fermentation of corn ballast. The amylose content in corn ballast starch reduced at first after natural fermentation, then grew, following the same trend as solubility. There were certain erosion marks on the surfaces of fermented corn ballast starch granules. The crystalline structure of corn ballast starch remained the same, i.e., a typical A-type crystalline structure, at different fermentation times; however, the intensities of diffraction peaks were different. The weight-average molecular weight of starch first increased and then decreased after fermentation. The content of low-molecular-weight starch (peak 3) decreased from 25.59 to 24.7% and then increased to 25.76%, while the content of high-molecular-weight starch (peak 1) increased from 51.45 to 53.26%, and then decreased to 52.52%. The fermentation time showed a negative correlation with the viscosity of starch, and the pasting temperature first increased, and then decreased. Natural fermentation can be used as a technical means to produce corn starch products as a result of the experiments' findings, and future experiments will detect and analyze the bacterial structure of corn fermentation broth in order to better understand the molecular mechanism of natural fermentation affecting the structure and physicochemical properties of corn starch.
Lactobacillus plantarum PL-02 Supplementation Combined With Resistance Training Improved Muscle Mass, Force, and Exercise Performance in Mice
Authors: Yeh Wen-Ling , Hsu Yi-Ju , Ho Chin-Shen , Ho Hsieh-Hsun , Kuo Yi-Wei , Tsai Shin-Yu , Huang Chi-Chang , Lee Mon-Chien
Published: April 2022

Increasing numbers of researchers are investigating the benefits of probiotics in enhancing exercise performance and verifying the role of the gut–muscle axis. In our previous study, Lactobacillus plantarum PL-02 improved exercise performance and muscle mass. Therefore, the purpose of this study was to investigate whether supplementation with PL-02 combined with resistance training has a synergistic effect on exercise performance and muscle mass. All the animals were assigned into four groups (n = 8/group): a sedentary control with normal distilled water group (vehicle, n = 8); PL-02 supplementation group (PL-02, 2.05 × 109 CFU, n = 8); resistance training group (RT, n = 8); PL-02 supplementation combined with resistance training group (PL-02 + RT, 2.05 × 109 CFU, n = 8). Supplementation with PL-02 for four consecutive weeks combined with resistance exercise training significantly improved the grip strength and the maximum number of crawls; increased the time of exhaustive exercise; significantly reduced the time required for a single climb; and reduced the lactate, blood ammonia, creatine kinase, and blood urea nitrogen produced after exercise (p < 0.05). In addition, it produced substantial benefits for increasing muscle mass without causing any physical damage. In summary, our findings confirmed that PL-02 or RT supplementation alone is effective in improving muscle mass and exercise performance and in reducing exercise fatigue, but the combination of the two can achieve increased benefits.
Navigational Transmaxillary Endoscopic Approach for Inferomedial Tumors
Authors: Wu Cheng-Hsien , Ho Yi-Yun , Liu Tzu-Lun , Wu Tzu-Ying , Cheng Han-Chieh , Tsai Chieh-Chih
Published: April 2022

Orbital tumors encompass a heterogeneous range of histopathology and usually variable in location. Traditionally, transconjunctival medial orbitotomy is used to access the medial orbital wall. However, it creates potential risk of soft tissue sequelae such as scarring, lid contracture, or entropion/ectropion. For the lesions close to the orbital apex, increased risk of optical nerve injury should be cautious during orbitotomy procedure. Transnasal endoscopic approach to the orbital walls has been applied since 1999. Although it provides good surgical visualization and prevents the soft tissue and neural complications, the narrow nasal corridor increases the surgical complexity. Extensive sphenoethmoidectomy is usually required to gaining access. Furthermore, the resultant medical orbital defect is difficult to repair. The maxillary sinus is the largest paranasal sinuses which is located beneath the orbital floor. It provides an ample working space for instrumentation. Meanwhile, repair of the orbital floor defect is feasible and with high degree of accuracy under navigation control. In this report, we propose a novel computer-assisted endoscopic protocol to excise the medial orbital tumors with immediate repair of the wall defect.
Construction of a Prognostic Model for Hypoxia-Related LncRNAs and Prediction of the Immune Landscape in the Digestive System Pan-Cancer
Authors: He Zikang , Liu Hongfeng , Guan Huilin , Ji Jinli , Jiang Ying , Zhang Naiwen , Song Zheyao , Wang Xingyun , Shen Ping , Wang Huan , Cui Rongjun
Published: April 2022

Digestive system pan-cancer is a general term for digestive system tumors including colorectal carcinoma (CRC), esophageal carcinoma (ESCA), stomach adenocarcinoma (STAD), and liver hepatocellular carcinoma (LIHC). Since the anatomical location, function and metabolism are closely related, there may be similarities in development and progression of these tumors. Hypoxia is the consequence of an imbalance between oxygen demand and supply, and intracellular hypoxia is associated with malignant progression, treatment resistance, and poor prognosis in tumors. Therefore, an urgent and challenging task is to investigate the molecular mechanisms associated with hypoxia in digestive system pan-cancer for the prognosis and treatment of digestive tract tumors. In this study, we identified 18 hypoxia-related lncRNAs (HRlncRNAs) by co-expression analysis between hypoxia genes and lncRNAs from digestive system pan-cancer. Six HRlncRNAs were then obtained using lasso regression and multivariate cox analysis to construct a prognostic model. Next, the Akaike information criterion (AIC) values for 3-year receiver operating curve (ROC) were counted to determine the cut-off point and establish an optimal model to distinguish between high- or low-risk groups among patients with digestive system pan-cancer. To evaluate the stability of the prognosis model, we validated it in terms of survival outcomes, clinicopathological stage, tumor-infiltrating immune cells, immune checkpoint inhibitors (ICIs) and anticancer drugs sensitivity. The results suggested that high- risk group had a worse prognosis and a more positive association with tumor-infiltrating immune cells such as B cells, cancer-associated fibroblasts, endothelial cells, monocytes, macrophages and bone marrow dendritic cells in digestive system pan-cancer. Immune checkpoint inhibitors (ICIs) related biomarkers discovered that high-risk group was positively correlated with high expression of HAVCR2 in digestive system pan-cancer. The anticancer drugs sensitivity analysis showed that the high-risk group was associated with the lower half-inhibitory centration (IC50) of Imatinib in digestive system pan-cancer. In conclusion, the prognostic model of HRlncRNAs showed a promising clinical prediction value and may provide a useful reference for the diagnosis and treatment of the digestive system tumors.
Efficacy and Safety for the Use of Half-Dosed Pegylated Granulocyte Colony-Stimulating Factors in Preventing Febrile Neutropenia During Chemotherapy in Patients With Malignant Tumors: A Multicenter, Open-Labeled, Single-Arm Phase 2 Trial
Authors: Mei Qi , Li Xiaoyu , Wang Runkun , Qin Kai , Cheng Yi , Cheng Weiting , Dong Youhong , He Zhen , Li Jun , Li Ming , Tang Xi , Wang Xudong , Xiao Xuxuan , Yang Bin , Zhou Yajuan , Wang Rui , Huang Qiao , Hu Guangyuan , Li Jian
Published: April 2022

Background

Prophylactic granulocyte-colony stimulating factor (G-CSF) has been shown to effectively prevent febrile neutropenia (FN) and grade 3/4 neutropenia during myelosuppressive treatment. The present study reports the clinical efficacy and safety of the prophylactic use of G-CSF with a half dose for cancer patients with an intermediate risk of FN combined with ≥1 patient-specific risk during multiple chemotherapy.

Methods

This multicenter, one-arm, and open-label clinical study involved 151 patients [median age, 54 years old (range, 46.0–62.5); 38.4% female] with malignant tumors, including >20 different cancers. These patients underwent a total of 604 cycles of chemotherapy and received a half dose of PEG-rhG-CSF administration prior to each cycle.

Results

The incidence rate of FN was 3.3% for this cohort during chemotherapy. Chemotherapy delay occurred in 6 (4.0%) patients for 12 (2.0%) cycles. Early termination of cancer treatment occurred in 14 (9.3%) patients. In this cohort, 23 (15.2%) patients required antibiotic use during courses of chemotherapy. A total of 28 (18.5%) patients experienced clear adverse effects during cancer treatment.

Conclusion

The prophylactic PEG-rhG-CSF with a half dose can both efficaciously and safely prevent neutropenia for patients of diverse cancers with an intermediate risk of FN combined with ≥1 patient-specific risk during chemotherapy.
A Prognostic Gene Signature for Hepatocellular Carcinoma
Authors: Chen Rong , Zhao Meng , An Yanli , Liu Dongfang , Tang Qiusha , Teng Gaojun
Published: April 2022

Hepatocellular carcinoma is the third most common cause of cancer-related deaths in China and immune-based therapy can improve patient outcomes. In this study, we investigated the relationship between immunity-associated genes and hepatocellular carcinoma from the prognostic perspective. The data downloaded from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) and the Gene Expression Omnibus (GEO) was screened for gene mutation frequency using the maftools package. Immunity-associated eight-gene signature with strong prognostic ability was constructed and proved as an independent predictor of the patient outcome in LIHC. Seven genes in the immune-related eight-gene signature were strongly associated with the infiltration of M0 macrophages, resting mast cells, and regulatory T cells. Our research may provide clinicians with a quantitative method to predict the prognosis of patients with liver cancer, which can assist in the selection of the optimal treatment plan.
Cancer/Testis Antigens as Biomarker and Target for the Diagnosis, Prognosis, and Therapy of Lung Cancer
Authors: Yang Ping , Qiao Yingnan , Meng Mei , Zhou Quansheng
Published: April 2022

Lung cancer is the leading type of malignant tumour among cancer-caused death worldwide, and the 5-year survival rate of lung cancer patients is only 18%. Various oncogenes are abnormally overexpressed in lung cancer, including cancer/testis antigens (CTAs), which are restrictively expressed in the male testis but are hardly expressed in other normal tissues, if at all. CTAs are aberrantly overexpressed in various types of cancer, with more than 60 CTAs abnormally overexpressed in lung cancer. Overexpression of oncogenic CTAs drives the initiation, metastasis and progression of lung cancer, and is closely associated with poor prognosis in cancer patients. Several CTAs, such as XAGE, SPAG9 and AKAP4, have been considered as biomarkers for the diagnosis and prognostic prediction of lung cancer. More interestingly, due to the high immunogenicity and specificity of CTAs in cancer, several CTAs, including CT45, BCAP31 and ACTL8, have been targeted for developing novel therapeutics against cancer. CTA-based vaccines, chimeric antigen receptor-modified T cells (CAR-T) and small molecules have been used in lung cancer treatment in pre-clinical and early clinical trials, with encouraging results being obtained. However, there are still many hurdles to be overcome before these therapeutics can be routinely used in clinical lung cancer therapy. This review summarises the recent rapid progress in oncogenic CTAs, focusing on CTAs as biomarkers for lung cancer diagnosis and prognostic prediction, and as targets for novel anti-cancer drug discovery and lung cancer therapy. We also identify challenges and opportunities in CTA-based cancer diagnosis and treatment. Finally, we provide perspectives on the mechanisms of oncogenic CTAs in lung cancer development, and we also suggest CTAs as a new platform for lung cancer diagnosis, prognostic prediction, and novel anti-cancer drug discovery.
MCF10CA Breast Cancer Cells Utilize Hyaluronan-Coated EV-Rich Trails for Coordinated Migration
Authors: Aaltonen Niina , Kyykallio Heikki , Tollis Sylvain , Capra Janne , Hartikainen Jaana M. , Matilainen Johanna , Oikari Sanna , Rilla Kirsi
Published: April 2022

Invasion of tumor cells through the stroma is coordinated in response to migratory cues provided by the extracellular environment. One of the most abundant molecules in the tumor microenvironment is hyaluronan, a glycosaminoglycan known to promote many hallmarks of tumor progression, including the migratory potential of tumor cells. Strikingly, hyaluronan is also often found to coat extracellular vesicles (EVs) that originate from plasma membrane tentacles of tumor cells crucial for migration, such as filopodia, and are abundant in tumor niches. Thus, it is possible that hyaluronan and hyaluronan-coated EVs have a cooperative role in promoting migration. In this work, we compared the hyaluronan synthesis, EV secretion and migratory behavior of normal and aggressive breast cell lines from MCF10 series. Single live cell confocal imaging, electron microscopy and correlative light and electron microscopy experiments revealed that migrating tumor cells form EV-rich and hyaluronan -coated trails. These trails promote the pathfinding behavior of follower cells, which is dependent on hyaluronan. Specifically, we demonstrated that plasma membrane protrusions and EVs left behind by tumor cells during migration are strongly positive for CD9. Single cell tracking demonstrated a leader-follower behavior, which was significantly decreased upon removal of pericellular hyaluronan, indicating that hyaluronan promotes the pathfinding behavior of follower cells. Chick chorioallantoic membrane assays in ovo suggest that tumor cells behave similarly in 3D conditions. This study strengthens the important role of extracellular matrix production and architecture in coordinated tumor cell movements and validates the role of EVs as important components and regulators of tumor matrix. The results suggest that tumor cells can modify the extracellular niche by forming trails, which they subsequently follow coordinatively. Future studies will clarify in more detail the orchestrated role of hyaluronan, EVs and other extracellular cues in coordinated migration and pathfinding behavior of follower cells.
Selective Targeting of Serotonin 5-HT1a and 5-HT3 Receptors Attenuates Acute and Long-Term Hypersensitivity Associated With Neonatal Procedural Pain
Authors: de Kort Anne R. , Joosten Elbert A. , Patijn Jacob , Tibboel Dick , van den Hoogen Nynke J.
Published: April 2022

Neonatal painful procedures causes acute pain and trigger long-term changes in nociceptive processing and anxiety behavior, highlighting the need for adequate analgesia during this critical time. Spinal serotonergic receptors 5-HT1a and 5-HT3 play an important role in modulating incoming nociceptive signals in neonates. The current study aims to attenuate acute and long-term hypersensitivity associated with neonatal procedural pain using ondansetron (a 5-HT3 antagonist) and buspirone (a 5-HT1a agonist) in a well-established rat model of repetitive needle pricking. Sprague-Dawley rat pups of both sexes received ondansetron (3 mg/kg), buspirone (3 mg/kg) or saline prior to repetitive needle pricks into the left hind-paw from postnatal day 0–7. Control animals received tactile stimulation or were left undisturbed. Acute, long-term, and post-operative mechanical sensitivity as well as adult anxiety were assessed. Neonatal 5-HT1a receptor agonism completely reverses acute hypersensitivity from P0-7. The increased duration of postoperative hypersensitivity after re-injury in adulthood is abolished by 5-HT3 receptor antagonism during neonatal repetitive needle pricking, without affecting baseline sensitivity. Moreover, 5-HT1a and 5-HT3 receptor modulation decreases adult state anxiety. Altogether, our data suggests that targeted pharmacological treatment based on the modulation of spinal serotonergic network via the 5-HT1a and 5-HT3 receptors in neonates may be of use in treatment of neonatal procedural pain and its long-term consequences. This may result in a new mechanism-based therapeutic venue in treatment of procedural pain in human neonates.
Kinesiophobia Predicts Physical Function and Physical Activity Levels in Chronic Pain-Free Older Adults
Authors: Naugle Kelly M. , Blythe Corinthian , Naugle Keith E. , Keith NiCole , Riley Zachary A.
Published: April 2022

Advanced aging is associated with a general decline in physical function and physical activity. The current evidence suggests that pain-related fear of movement (i.e., kinesiophobia) is increased in the general older adult population and impacts physical activity levels in patients with chronic pain. However, whether kinesiophobia could impact physical activity and function in relatively healthy, chronic pain-free older adults remain unclear. Thus, the purpose of this study was to examine whether fear of movement due to pain predicted self-reported and objective levels of physical function and physical activity in healthy older adults without chronic pain. Fifty-two older adults were enrolled in this study. The participants completed the International Physical Activity Questionnaire (IPAQ) and wore an accelerometer on the hip for 7 days to measure physical activity. Measures of sedentary time, light physical activity, and moderate to vigorous physical activity were obtained from the accelerometer. Measures of physical function included the Physical Functioning subscale of the Short Form-36, Short Physical Performance Battery (SPPB), the 30-s Chair Stand test, and a maximal isometric hand-grip. The Tampa Scale of Kinesiophobia (TSK) was used to measure fear of movement or re-injury associated with pain. Potential covariates included self-reported activity-related pain and demographics. Hierarchical linear regressions were conducted to determine the relationship of kinesiophobia with levels of physical activity and physical function while controlling for activity-related pain and demographics. TSK scores did not predict self-reported physical activity on the IPAQ. However, TSK scores predicted self-reported physical function (Beta = −0.291, p = 0.015), 30-s Chair Stand test scores (Beta = −0.447, p = 0.001), measures from the SPPB (Gait speed time: Beta = 0.486, p < 0.001; Chair stand time: Beta = 0.423, p = 0.003), percentage of time spent in sedentary time (Beta = 0.420, p = 0.002) and light physical activity (Beta = −0.350, p = 0.008), and moderate to vigorous physical activity (Beta = −0.271, p = 0.044), even after controlling for significant covariates. These results suggest that greater pain-related fear of movement/re-injury is associated with lower levels of light and moderate to vigorous physical activity, greater sedentary behavior, and worse physical function in healthy, chronic pain-free older adults. These findings elucidate the potential negative impact of kinesiophobia in older adults who don't report chronic pain.
Comparison of the Dual Therapy of Ilaprazole-Amoxicillin and the Bismuth Quadruple Therapy of Ilaprazole-Amoxicillin-Furazolidone-Bismuth Glycyrrhizinate for Eradication of Helicobacter pylori
Authors: Niu Min , Zhou Yan , Xie Yunqian , Li Xue , Tian Yonggang , Yao Li , Li Ximei , Gao Hengjun , Bai Feihu
Published: April 2022

Objective: The present study aims to compare the safety and efficacy of an amoxicillin/ilaprazole regimen with a bismuth quadruple regimen as the first-line treatment for eradicating Helicobacter pylori (H. pylori) infection.

Methods: This was an open-label, randomized, single-center study involving 450 patients with untreated H. pylori infection who were randomly assigned to an Ilaprazole-amoxicillin-furazolidone-bismuth glycyrrhizinate (IAFB) quadruple therapy group for 14 days, a bismuth quadruple therapy group for 10 days, or Ilaprazole-amoxicillin (IA) dual therapy group for 14 days. The 13C urea breath test determined that H. pylori had been eliminated 4–6 weeks after treatment. For patients who failed the first treatment, mucosal tissues (two gastric antrum and one gastric body) were taken under gastroscope for the culture of H. pylori, drug sensitivity, the CYP2C19 gene, and globular degeneration.

Results: In the intention-to-treat analysis, the eradication rates of H. pylori in the IAFB-14-day group, the IAFB-10-day group, and the IA-14-day group were 84.0, 79.3, and 88.0%, respectively. In the per-protocol analysis, the eradication rates in the three groups were 94.7, 87.5, and 93.0%, respectively. The resistance rates of patients who failed H. pylori eradication were 68.9% (22/32) for amoxicillin, 90.6% (29/32) for clarithromycin, 68.9% (22/32) for metronidazole, and 87.5% (28/32) for levofloxacin, and the extensive metabolizers of CYP2C19 polymorphism were 59.3% (19/32), the intermediate metabolizers were 34.4% (11/32), and the poor metabolizers were 6.3% (2/32).

Conclusion: For newly treated patients with H. pylori infection in China, the efficacy of IA therapy for 14 days was similar to IAFB quadruple therapy for 10 or 14 days with better compliance and less cost. Therefore, these therapies can be considered first-line regimens for empirical treatment.

Clinical Trial Registration: [http://www.chictr.org.cn/searchproj.aspx], identifier [ChiCTR2100052308].
Acute and Long-Term Treatment With Dapagliflozin and Association With Serum Soluble Urokinase Plasminogen Activator Receptor
Authors: Rotbain Curovic Viktor , Houlind Morten B. , Hansen Tine W. , Eugen-Olsen Jesper , Laursen Jens Christian , Eickhoff Mie K. , Persson Frederik , Rossing Peter
Published: April 2022

Background: Elevated soluble urokinase plasminogen activator receptor (suPAR) is highly associated with increased risk of diabetic complications. Dapagliflozin is a drug inhibiting the sodium-glucose co-transporter 2 in the kidney to decrease blood glucose, while also decreasing risk of kidney disease, heart failure, and death. Therefore, we have investigated suPAR as a monitor for treatment effect with dapagliflozin in diabetes.

Methods: suPAR was measured in two double-blinded randomized clinical cross-over trials. The first trial investigated the effect of a single dose dapagliflozin 50 mg or placebo 12 h after intake, in individuals with type 1 diabetes and albuminuria. The second trial investigated the effect of a daily dose dapagliflozin 10 mg or placebo for 12 weeks, in individuals with type 2 diabetes and albuminuria. suPAR was measured in serum samples taken, in the acute trial, after treatment with dapagliflozin and placebo, and in the long-term trial, before and after treatment with dapagliflozin and placebo. Effect of dapagliflozin on suPAR levels were assessed using paired t-test.

Results: 15 participants completed the acute trial and 35 completed the long-term trial. Mean difference in suPAR between dapagliflozin and placebo in the acute trial after 12 h was 0.70 ng/ml (95% CI: 0.66; 1.33, p = 0.49). In the long-term trial the mean difference was 0.06 ng/ml (95% CI -0.15; 0.27, p = 0.57).

Conclusion: Based on our findings we conclude that suPAR is not a feasible marker to monitor the effect of treatment with dapagliflozin. Thus, a further search of suitable markers must continue.
Sodium Tanshinone IIA Sulfonate as a Potent IDO1/TDO2 Dual Inhibitor Enhances Anti-PD1 Therapy for Colorectal Cancer in Mice
Authors: Zhang Rongjie , Wang Yuanfeiyi , Liu Dan , Luo Qing , Du Peixin , Zhang Haiyan , Wu Wenshuang
Published: April 2022

Although the antitumor efficacy of immune checkpoint blockade (ICB) has been proved in colorectal cancer (CRC), the results are unsatisfactory, presumably owing to the presence of tryptophan metabolism enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2). However, only a few dual inhibitors for IDO1 and TDO2 have been reported. Here, we discovered that sodium tanshinone IIA sulfonate (STS), a sulfonate derived from tanshinone IIA (TSN), reduced the enzymatic activities of IDO1 and TDO2 with a half inhibitory concentration (IC50) of less than 10 μM using enzymatic assays for natural product screening. In IDO1- or TDO2- overexpressing cell lines, STS decreased kynurenine (kyn) synthesis. STS also reduced the percentage of forkhead box P3 (FOXP3) T cells in lymphocytes from the mouse spleen cocultured with CT26. In vivo, STS suppressed tumor growth and enhanced the antitumor effect of the programmed cell death 1 (PD1) antibody. Compared with anti-PD1 (α-PD1) monotherapy, combined with STS had lower level of plasma kynurenine. Immunofluorescence assay suggested that STS decreased the number of FOXP3+ T cells and increased the number of CD8+ T cells in tumors. Flow cytometry analysis of immune cells in tumor tissues demonstrated an increase in the percentage of tumor-infiltrating CD8+ T cells. According to our findings, STS acts as an immunotherapy agent in CRC by inhibiting both IDO1 and TDO2.
Examination of Complementary Medicine for Treating Urinary Tract Infections Among Pregnant Women and Children
Authors: Hudson Rachel E. , Job Kathleen M. , Sayre Casey L. , Krepkova Lubov V. , Sherwin Catherine M. , Enioutina Elena Y.
Published: April 2022

Urinary tract infections (UTIs) are a significant clinical problem that pregnant women and children commonly experience. Escherichia coli is the primary causative organism, along with several other gram-negative and gram-positive bacteria. Antimicrobial drugs are commonly prescribed to treat UTIs in these patients. Conventional treatment can range from using broad-spectrum antimicrobial drugs for empirical or prophylactic therapy or patient-tailored therapy based on urinary cultures and sensitivity to prospective antibiotics. The ongoing emergence of multi-drug resistant pathogens has raised concerns related to commonly prescribed antimicrobial drugs such as those used routinely to treat UTIs. Consequently, several natural medicines have been explored as potential complementary therapies to improve health outcomes in patients with UTIs. This review discusses the effectiveness of commonly used natural products such as cranberry juice/extracts, ascorbic acid, hyaluronic acid, probiotics, and multi-component formulations intended to treat and prevent UTIs. The combination of natural products with prescribed antimicrobial treatments and use of formulations that contained high amounts of cranberry extracts appear to be most effective in preventing recurrent UTIs (RUTIs). The incorporation of natural products like cranberry, hyaluronic acid, ascorbic acid, probiotics, Canephron® N, and Cystenium II to conventional treatments of acute UTIs or as a prophylactic regimen for treatment RUTIs can benefit both pregnant women and children. Limited information is available on the safety of natural products in these patients’ populations. However, based on limited historical information, these remedies appear to be safe and well-tolerated by patients.
Effect of Baicalein on the Pharmacokinetics of Cilostazol and Its Two Metabolites in Rat Plasma Using UPLC-MS/MS Method
Authors: Weng Qinghua , Chen Chaojie , Xiong Jianhua , Liu Ya-Nan , Pan Xinxin , Cui Ju , Cai Jian-Ping , Xu Ren-Ai
Published: April 2022

This study aimed to explore the effect of baicalein on the pharmacokinetics of cilostazol (CLZ) and its two metabolites 3,4-dehydro cilostazol (3,4-CLZ) and 4′-trans-hydroxy cilostazol (4′-CLZ) in rats using a newly established ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. Ticagrelor was used as an internal standard (IS), then cilostazol and its two metabolites were separated by means of a UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) using gradient elution method with 0.4 ml/min of flow rate. Acetonitrile as organic phase and water with 0.1% formic acid as aqueous phase constructed the mobile phase. Selective reaction monitoring (SRM) mode and positive ion mode were preferentially chosen to detect the analytes. Twelve SD rats were divided into two groups (n = 6) when CLZ was administered orally (10 mg/kg) with or without oral baicalein (80 mg/kg). The selectivity, linearity, recovery, accuracy, precision, matrix effect and stability of UPLC-MS/MS assay were satisfied with the standards of United States Food and Drug Administration guidelines. In control group, AUC0-∞ and Cmax of CLZ were 2,169.5 ± 363.1 ng/ml*h and 258.9 ± 82.6 ng/ml, respectively. The corresponding results were 3,767.6 ± 1,049.8 ng/ml*h and 308.6 ± 87.9 ng/ml for 3, 4-CLZ, 728.8 ± 189.9 ng/ml*h and 100.3 ± 51.3 ng/ml for 4′-CLZ, respectively. After combination with baicalein, AUC0-∞ and Cmax of CLZ were 1.48, 1.38 times higher than the controls. Additionally, AUC0-∞ and Cmax were separately decreased by 36.12 and 19.54% for 3,4-CLZ, 13.11 and 44.37% for 4′-CLZ. Baicalein obviously alters the pharmacokinetic parameters of CLZ, 3,4-CLZ and 4′-CLZ in rats. These results suggested that there was a potential drug-drug interaction between baicalein and CLZ. Therefore, it must raise the awareness when concomitant use of CLZ with baicalein, the dosage regimen of CLZ should be taken into consideration, if this result is confirmed in clinical studies.
Highly Efficient Metasurface Polarization Converter at Far-Infrared Range
Authors: Tamim Ahmed Mahfuz , Hasan Md Mehedi , Faruque Mohammad Rashed Iqbal
Published: April 2022

Controlling the polarization state is an efficient way to enhance the functionalities in sensing, imaging, and communication systems in the microwave and terahertz (THz) spectrum. This study proposed an anisotropic metasurface and numerically explained it as a highly efficient polarization conversion using far-infrared frequency. Structural design, optimization, and results examination of the metasurface are performed using the CST microwave studio electromagnetic simulator. The metasurface was developed surrounding the two individual arrow-shaped metal resonators with two bar resonators on the opposite angular side of the arrow. Aluminum (Al) was used as a metallic resonator, while gallium arsenide (GaAs) was as the substrate. The interference theory was used to describe the co-polarized and cross-polarized reflectance coefficients, where two different mediums and interference layers were considered along with the reflected and transmitted wave. The polarization conversion efficiency yielded over 90% from 282.9 to 302.3 µm (0.987–1.062 THz) and 558.78 to 676.7 µm (0.442–0.537 THz) indicating multiple resonances at 286.7, 298.25, 586.1, and 689.55 µm. In conclusion, the performances and diverse characteristics of the designed metasurface demonstrated potential applications in the far-infrared spectrum as an efficient polarization converter application.