bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes and Treatment Complications of Intravenous Urokinase Thrombolysis in Acute Ischemic Stroke in China
Authors: Zhang Rongrong , Wei Hui , Ren Yu , Wu Yanping , Luo Yetao , Zhang Lei , Huo Yingchao , Feng Jinzhou , Monnier Philippe P. , Qin Xinyue
Published: July 2021

Background: Intravenous thrombolysis with alteplase benefits eligible patients with acute ischemic stroke. However, in some countries such as China, alteplase may be too expensive for low-income patients, and also for regions with low economic development. Urokinase is much less expensive than alteplase. This study aimed to assess the outcomes and treatment complications of urokinase in acute ischemic stroke patients, which are poorly understood.

Methods: This multicenter retrospective study included acute ischemic stroke patients who received intravenous urokinase or alteplase from January 2014 to January 2018 at 21 centers in China. Outcomes and treatment complications were analyzed by univariate and multivariate analyses.

Results: Among the 618 patients included in this study, 489 were treated with urokinase and 129 were treated with alteplase. Functional independence, no/minimal disability, mortality, intracranial hemorrhage (ICH), and symptomatic ICH did not significantly differ between the urokinase and alteplase groups in the univariate and multivariate analyses. However, the patients who received alteplase had a lower odds ratio (OR) of extracranial bleeding in the univariate analysis and a lower adjusted OR (aOR) in the multivariate analysis than the patients who received urokinase (OR = 0.410 [95% CI, 0.172–0.977], p = 0.038; aOR = 0.350 [95% CI, 0.144–0.854], p = 0.021). Furthermore, in patients treated with urokinase, the patients who received high-dose urokinase had a higher OR of extracranial bleeding in the univariate analysis and a higher aOR of extracranial bleeding in the multivariate analysis than patients who received low-dose urokinase (OR = 3.046 [95% CI, 1.696–5.470], p < 0.001; aOR = 3.074 [95% CI, 1.627–5.807], p = 0.001). Moreover, patients who received low-dose urokinase had similar outcomes and complications compared to patients treated with alteplase.

Conclusions: Patients treated with urokinase had similar outcomes but a higher risk of extracranial bleeding compared to patients treated with alteplase. The risk of extracranial bleeding was higher in the patients treated with high-dose urokinase than in the patients treated with low-dose urokinase. Patients who received low-dose urokinase had similar outcomes and complications compared to patients treated with alteplase. In countries such as China where some acute ischemic stroke patients cannot afford alteplase, urokinase may be a good alternative to alteplase for intravenous thrombolysis.
Disrupted Topological Organization in White Matter Networks in Unilateral Sudden Sensorineural Hearing Loss
Authors: Zou Yan , Ma Hui , Liu Bo , Li Dan , Liu Dingxi , Wang Xinrong , Wang Siqi , Fan Wenliang , Han Ping
Published: July 2021

Sudden sensorineural hearing loss (SSNHL) is a sudden-onset hearing impairment that rapidly develops within 72 h and is mostly unilateral. Only a few patients can be identified with a defined cause by routine clinical examinations. Recently, some studies have shown that unilateral SSNHL is associated with alterations in the central nervous system. However, little is known about the topological organization of white matter (WM) networks in unilateral SSNHL patients in the acute phase. In this study, 145 patients with SSNHL and 91 age-, gender-, and education-matched healthy controls were evaluated using diffusion tensor imaging (DTI) and graph theoretical approaches. The topological properties of WM networks, including global and nodal parameters, were investigated. At the global level, SSNHL patients displayed decreased clustering coefficient, local efficiency, global efficiency, normalized clustering coefficient, normalized characteristic path length, and small-worldness and increased characteristic path length (p < 0.05) compared with healthy controls. At the nodal level, altered nodal centralities in brain regions involved the auditory network, visual network, attention network, default mode network (DMN), sensorimotor network, and subcortical network (p < 0.05, Bonferroni corrected). These findings indicate a shift of the WM network topology in SSNHL patients toward randomization, which is characterized by decreased global network integration and segregation and is reflected by decreased global connectivity and altered nodal centralities. This study could help us understand the potential pathophysiology of unilateral SSNHL.
The Impact of Voluntary Exercise on Stroke Recovery
Authors: Lohkamp Klara J. , Kiliaan Amanda J. , Shenk Justin , Verweij Vivienne , Wiesmann Maximilian
Published: July 2021

Stroke treatment is limited to time-critical thrombectomy and rehabilitation by physiotherapy. Studies report beneficial effects of exercise; however, a knowledge gap exists regarding underlying mechanisms that benefit recovery of brain networks and cognition. This study aims to unravel therapeutic effects of voluntary exercise in stroke-induced mice to develop better personalized treatments. Male C57Bl6/JOlaHsd mice were subjected to transient middle cerebral artery occlusion. After surgery, the animals were divided in a voluntary exercise group with access to running wheels (RW), and a control group without running wheels (NRW). During 6 days post-stroke, activity/walking patterns were measured 24/7 in digital ventilated cages. Day 7 post-surgery, animals underwent MRI scanning (11.7T) to investigate functional connectivity (rsfMRI) and white matter (WM) integrity (DTI). Additionally, postmortem polarized light imaging (PLI) was performed to quantify WM fiber density and orientation. After MRI the animals were sacrificed and neuroinflammation and cerebral vascularisation studied. Voluntary exercise promoted myelin density recovery corresponding to higher fractional anisotropy. The deteriorating impact of stroke on WM dispersion was detected only in NRW mice. Moreover, rsfMRI revealed increased functional connectivity, cerebral blood flow and vascular quality leading to improved motor skills in the RW group. Furthermore, voluntary exercise showed immunomodulatory properties post-stroke. This study not only helped determining the therapeutic value of voluntary exercise, but also provided understanding of pathological mechanisms involved in stroke.
Foveal Remodeling of Retinal Microvasculature in Parkinson’s Disease
Authors: Murueta-Goyena Ane , Barrenechea Maitane , Erramuzpe Asier , Teijeira-Portas Sara , Pengo Marta , Ayala Unai , Romero-Bascones David , Acera Marian , Del Pino Rocío , Gómez-Esteban Juan Carlos , Gabilondo Iñigo
Published: July 2021

Background

Retinal microvascular alterations have been previously described in Parkinson’s disease (PD) patients using optical coherence tomography angiography (OCT-A). However, an extensive description of retinal vascular morphological features, their association with PD-related clinical variables and their potential use as diagnostic biomarkers has not been explored.

Methods

We performed a cross-sectional study including 49 PD patients (87 eyes) and 40 controls (73 eyes). Retinal microvasculature was evaluated with Spectralis OCT-A and cognitive status with Montreal Cognitive Assessment. Unified PD Rating Scale and disease duration were recorded in patients. We extracted microvascular parameters from superficial and deep vascular plexuses of the macula, including the area and circularity of foveal avascular zone (FAZ), skeleton density, perfusion density, vessel perimeter index, vessel mean diameter, fractal dimension (FD) and lacunarity using Python and MATLAB. We compared the microvascular parameters between groups and explored their association with thickness of macular layers and clinical outcomes. Data were analyzed with General Estimating Equations (GEE) and adjusted for age, sex, and hypertension. Logistic regression GEE models were fitted to predict diagnosis of PD versus controls from microvascular, demographic, and clinical data. The discrimination ability of models was tested with receiver operating characteristic curves.

Results

FAZ area was significantly smaller in patients compared to controls in superficial and deep plexuses, whereas perfusion density, skeleton density, FD and lacunarity of capillaries were increased in the foveal zone of PD. In the parafovea, microvascular parameters of superficial plexus were associated with ganglion cell-inner plexiform layer thickness, but this was mainly driven by PD with mild cognitive impairment. No such associations were observed in controls. FAZ area was negatively associated with cognition in PD (non-adjusted models). Foveal lacunarity, combined with demographic and clinical confounding factors, yielded an outstanding diagnostic accuracy for discriminating PD patients from controls.

Conclusion

Parkinson’s disease patients displayed foveal microvascular alterations causing an enlargement of the vascular bed surrounding FAZ. Parafoveal microvascular alterations were less pronounced but were related to inner retinal layer thinning. Retinal microvascular abnormalities helped discriminating PD from controls. All this supports OCT-A as a potential non-invasive biomarker to reveal vascular pathophysiology and improve diagnostic accuracy in PD.
Metabolism of Tracer 75Se Selenium From Inorganic and Organic Selenocompounds Into Selenoproteins in Rats, and the Missing 75Se Metabolites
Authors: Evenson Jacqueline K. , Sunde Roger A.
Published: July 2021

We now know much about selenium (Se) incorporation into selenoproteins, and there is considerable interest in the optimum form of Se for supplementation and prevention of cancer. To study the flux of 75Se into selenoprotein, rats were fed 0 to 5 μg Se/g diet as selenite for 50–80 d and injected iv with 50 μCi of 75Se-labeled selenite, selenate, selenodiglutathione, selenomethionine, or selenobetaine at tracer levels (~0.5 μg Se). The rats were killed at various times and 75Se incorporation into selenoproteins was assessed by SDS/PAGE. These studies found that there is very rapid Se metabolism from this diverse set of selenocompounds to the common intermediate used for synthesis and incorporation of 75Se into the major selenoproteins in a variety of tissues. No selenocompound was uniquely or preferentially metabolized to provide Se for selenoprotein incorporation. Examination of the SDS/PAGE selenoprotein profiles, however, reveals that synthesis of selenoproteins is only part of the full Se metabolism story. The 75Se missing from the selenoprotein profiles, especially at early timepoints, is likely to be both low-MW and high-MW selenosugars and related precursors, as we recently found in livers of turkeys fed Se-adequate and high-Se diets. Differential metabolism of different selenocompounds into different selenosugar species may occur; these species may be involved in prevention of cancer or other diseases linked to Se status and may be associated with Se toxicity. Additional studies using HPLC-mass spectroscopy will likely be needed to fully flesh out the complete metabolism of selenium.
Pan-Cancer Prognostic Role and Targeting Potential of the Estrogen-Progesterone Axis
Authors: Shen Yu-ting , Huang Xing , Zhang Gang , Jiang Bo , Li Cheng-jun , Wu Zheng-sheng
Published: July 2021

Introduction

Estrogen receptors (ESRs) and progesterone receptors (PGRs) are associated with the development and progression of various tumors. The feasibility of ESRs and PGRs as prognostic markers and therapeutic targets for multiple cancers was evaluated via pan-cancer analysis.

Methods

The pan-cancer mRNA expression levels, genetic variations, and prognostic values of ESR1, ESR2, and PGR were analyzed using the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) and cBioPortal. The expression levels of ERa, ERb, and PGR proteins were detected by immunohistochemical staining using paraffin-embedded tissue specimens of ovarian serous cystadenocarcinoma (OV) and uterine endometrioid adenocarcinoma (UTEA). Correlation between immunomodulators and immune cells was determined based on the Tumor and Immune System Interaction Database (TISIDB).

Results

ESR1, ESR2, and PGR mRNAs were found to be differentially expressed in different cancer types, and were associated with tumor progression and clinical prognosis. ERa, ERb, and PGR proteins were further determined to be significantly differentially expressed in OV and UTEA via immunohistochemical staining. The expression of ERa protein was positively correlated with a high tumor stage, whereas the expression of PGR protein was conversely associated with a high tumor stage in patients with OV. In patients with UTEA, the expression levels of both ERa and PGR proteins were conversely associated with tumor grade and stage. In addition, the expression levels of ESR1, ESR2, and PGR mRNAs were significantly associated with the expression of immunomodulators and immune cells.

Conclusion

ESR1, ESR2, and PGR are potential prognostic markers and therapeutic targets, as well as important factors for the prediction, evaluation, and individualized treatment in several cancer types.
Preoperative Prediction of Lymphovascular Space Invasion in Cervical Cancer With Radiomics –Based Nomogram
Authors: Du Wei , Wang Yu , Li Dongdong , Xia Xueming , Tan Qiaoyue , Xiong Xiaoming , Li Zhiping
Published: July 2021

Purpose

To build and evaluate a radiomics-based nomogram that improves the predictive performance of the LVSI in cervical cancer non-invasively before the operation.

Method

This study involved 149 patients who underwent surgery with cervical cancer from February 2017 to October 2019. Radiomics features were extracted from T2 weighted imaging (T2WI). The radiomic features were selected by logistic regression with the least absolute shrinkage and selection operator (LASSO) penalty in the training cohort. Based on the selected features, support vector machine (SVM) algorithm was used to build the radiomics signature on the training cohort. Incorporating radiomics signature and clinical risk factors, the radiomics-based nomogram was developed. The sensitivity, specificity, accuracy, and area under the curve (AUC) and Receiver operating characteristic (ROC) curve were calculated to assess these models.

Result

The radiomics model performed much better than the clinical model in both training (AUCs 0.925 vs. 0.786, accuracies 87.5% vs. 70.5%, sensitivities 83.6% vs. 41.7% and specificities 90.9% vs. 94.7%) and testing (AUCs 0.911 vs. 0.706, accuracies 84.0% vs. 71.3%, sensitivities 81.1% vs. 43.4% and specificities 86.4% vs. 95.0%). The combined model based on the radiomics signature and tumor stage, tumor infiltration depth and tumor pathology yielded the best performance (training cohort, AUC = 0.943, accuracies 89.5%, sensitivities 85.4% and specificities 92.9%; testing cohort, AUC = 0.923, accuracies 84.6%, sensitivities 84.0% and specificities 85.1%).

Conclusion

Radiomics-based nomogram was a useful tool for predicting LVSI of cervical cancer. This would aid the selection of the optimal therapeutic strategy and clinical decision-making for individuals.
Long Non-Coding RNA LINC01410 Promoted Tumor Progression via the ErbB Signaling Pathway by Targeting STAT5 in Gallbladder Cancer
Authors: Lu Lili , Zhang Shilong , Song Zhengqing , Lu Weiqi , Wang Zhiming , Zhou Yuhong
Published: July 2021

Objectives

Long non-coding RNAs (lncRNAs) have been recently emerging as crucial molecules in multiple human cancers. However, their expression patterns, roles as well as the underlying mechanisms in gallbladder cancer (GBC) remain largely unclear.

Materials and Methods

The expression of lncRNAs in GBC was downloaded from GEO database. Quantitative real-time polymerase chain reaction (qRT-PCR) and RNA in situ hybridization (ISH) were used to detect the expression of lncRNAs in GBC tissues. The full-sequence of LINC01410 was determined by RACE assay. Subcellular distribution of LINC01410 was examined by nuclear/cytoplasmic RNA fractionation analysis. Loss- and gain-of-function experiments were conducted to explore the biological functions of LINC01410 in vitro and in vivo. RNA pull-down, RNA immune-precipitation (RIP), and Western blot assay were conducted to investigate the mechanisms underlying the biological function of LINC01410 in GBC.

Results

LINC01410 was significantly upregulated in the GBC tissues compared to adjacent non-tumor tissues. High LINC01410 expression was significantly associated with poor prognosis of GBC patients. We identified LINC01410 to be 2,877 bp in length and mainly localized in the cytoplasm of GBC cells. Overexpression of LINC01410 promoted GBC cell proliferation, migration, and invasion in vitro and GBC progression in vivo, whereas LINC01410 downregulation rescued these effects in vitro. From RNA pull-down and RIP assay, we identified that STAT5 was a critical downstream target of LINC01410. Furthermore, ErbB signaling pathway was involved in the malignant phenotypes of GBC mediated by LINC01410.

Conclusions

Our results suggested that LINC01410 was an important lncRNA that promoted GBC progression via targeting STAT5 and activating ErbB signaling pathway.
Next-Generation Sequencing Enhances the Diagnosis Efficiency in Thyroid Nodules
Authors: Tan Li-Cheng , Liu Wan-Lin , Zhu Xiao-Li , Yu Peng-Cheng , Shi Xiao , Han Pei-Zhen , Zhang Ling , Lin Liang-Yu , Semenov Arseny , Wang Yu , Ji Qing-Hai , Ji Dong-Mei , Wang Yu-Long , Qu Ning
Published: July 2021

Background

Though fine-needle aspiration (FNA) improved the diagnostic methods of thyroid nodules, there are still parts of nodules that cannot be determined according to cytology. In the Bethesda system for reporting thyroid cytopathology, there are two uncertain cytology results. Thanks to the development of next-generation sequencing technology, it is possible to gain the genetic background of pathological tissue efficiently. Therefore, a combination of the cytology and genetic background may enhance the accuracy of diagnosis in thyroid nodules.

Methods

DNA from 73 FNA samples of thyroid nodules belonging to different cytology types was extracted and exome sequencing was performed by the ThyroLead panel. Test for BRAF mutation was also performed by ARMS-qPCR. Information including age, sex, preoperative cytology, BRAF mutation status tested by ARMS-qPCR, and surgical pathology was collected in electronic medical record system.

Results

A total of 71 single nucleotide variants, three fusion gene, and two microsatellite instability-high status were detected in 73 FNA samples. BRAF V600E mutation is the most common mutation in these malignant thyroid nodules. After combining the cytology and genetic background detected by next-generation sequencing, the diagnosis sensitivity was increased from 0.582 (95% CI: 0.441–0.711) to 0.855 (95% CI: 0.728–0.930) (P < 0.001) in our group, while the specificity, 1,000 (95% CI: 0.732–1.000) compared to 0.857 (95% CI: 0.562–0.975) (P = 0.25), did not get affected.

Conclusions

Next-generation sequencing in thyroid nodules can enhance the preoperative diagnosis sensitivity by fine-needle aspiration alone. It can also provide genetic background for direction of medication. It is possible for clinicians to combine cytology with genetic alterations for a more precise diagnosis strategy of thyroid nodules.
Development and Validation of Predicting Nomograms for Craniopharyngioma: A Retrospective, Multiple-Center, Cohort Study
Authors: Xu Dingkang , Wei Qingjie , Li Zhe , Hu Yan , Hu Peizhu , Zhao Shengqi , Song Dengpan , Lei Shixiong , Zhang Mingchu , Gao Qiang , Zhang Longxiao , Lin Fangbo , Zuo Yuchao , Liu Xianzhi , Feng Mengzhao , Ma Chunxiao , Guo Fuyou
Published: July 2021

Craniopharyngiomas (CPs) are benign tumors arising from the sellar region. However, little is known about their clinical features and long-term recurrence due to low morbidity and the lack of large cohort studies. Thus, we aimed to develop nomograms to accurately predict the extent of resection and tumor recurrence using clinical parameters. A total of 545 patients diagnosed with CP between 2009 and 2019 were examined: 381 in the development cohort and 164 in the validation cohort. Least absolute shrinkage and selection operator (LASSO) and Cox regression analyses were performed to establish two nomograms. Receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA) and Kaplan-Meier (KM) curves were used to evaluate their predictive performance and discriminative power, respectively, in the two cohorts. In addition, the EORTC QLQ-BN20 questionnaire was used to assess neuropsychological status in the follow-up. In the development cohort, the area under the curve (AUC) and C-index were 0.760 and 0.758, respectively, for predicting the extent of resection and 0.78 and 0.75, respectively, for predicting 3-year progression-free survival (PFS) and 5-year PFS. Additionally, the model had a predictive accuracy of 0.785. Both nomograms showed acceptable discrimination in the two cohorts. Moreover, DCA demonstrated excellent clinical benefits from the two nomograms. Finally, participants were classified into two distinct risk groups according to the risk score, and an online calculator was created for convenient clinical use. During long term follow-up, hypothyroidism (77.61%) and hypocortisolism (76.70%) were the most common endocrine dysfunction after surgery and significant deficits were observed concerning visual disorder, motor dysfunction and seizures in the recurrent groups. In particular, better quality of life was associated with gross total resection (GTR), postoperative radiation, anterior interhemispheric (AI) approach and transsphenoidal approach. To our knowledge, these are the first nomograms based on a very large cohort of patients with CP that show potential benefits for guiding treatment decisions and long-term surveillance. The current study demonstrated the online calculator serve as the practical tool for individual strategies based on the patient’s baseline characteristics to achieve a better prognosis.
Identification and Validation of a Novel Immune-Related lncRNA Signature for Bladder Cancer
Authors: Hua Shan , Xie Zhiwen , Wang Wenhao , Wan Zhong , Chen Min , Zhao Sheng , Jiang Juntao
Published: July 2021

Purpose

We aimed to construct an immune-related long noncoding ribonucleic acids (irlncRNA) signature to evaluate the prognosis of patients without specific expression level of these irlncRNA.

Methods

The raw transcriptome data were downloaded from The Cancer Genome Atlas (TCGA), irlncRNAs were filtered out using an online immune related gene database and coexpression analysis, differently expressed irlncRNA (DEirlncRNA) pairs were identified by univariate analysis. The areas under curve (AUC) were compared and the Akaike information criterion (AIC) values of receiver operating curve (ROC) was counted, the most optimal model was constructed to divide bladder cancer patients into high- and low-risk groups usingõ the cut-off point of ROC. Then, we evaluated them from multiple perspectives, such as survival time, clinic-pathological characteristics, immune-related cells infiltrating, chemotherapeutics efficacy and immune checkpoint inhibitors.

Results

14 DEirlncRNA pairs were included in this signature. Patients in high-risk groups demonstrated apparent shorter survival time, more aggressive clinic-pathological characteristics, different immune-related cells infiltrating status, lower chemotherapeutics efficacy.

Conclusion

The irlncRNA signature demonstrated a promising prediction value for bladder cancer patients and was important in guiding clinical treatment.
Pulmonary Vein Index Is Associated With Early Prognosis of Surgical Treatment for Tetralogy of Fallot
Authors: Yuan Haoyong , Qian Tao , Huang Ting , Yang Hui , Huang Can , Lu Ting , Wu Zhongshi
Published: July 2021

Objectives: To evaluate the predictive value of the pulmonary vein index (PVI) in the early prognosis of patients who received total tetralogy of Fallot (TOF) repair.

Methods: We retrospectively reviewed 286 patients who underwent TOF repair in our institution between July 2013 and May 2020. The PVI, McGoon ratio, and Nakata index were measured and calculated. Logistic regression, linear stepwise regression, receiver operating characteristic (ROC) curve analysis, and Cox proportional hazards modeling were performed to evaluate the predictive value of PVI in the early prognosis after TOF repair surgery.

Results: The median age and body weight were 1.23 (0.22–15.02) years and 9.00 (3.00–44.00) kg, respectively. There were five early deaths. The areas under the ROC curve for death were 0.89, 0.79, and 0.88 for the McGoon ratio, Nakata index, and PVI, respectively. A lower PVI better predicted prolonged postoperative hospital stay, cardiac intensive care unit stay, and ventilator time (Hazard Ratio, HR [95% Confidence intervals, CI]: 1.003 [1.002–1.004], p < 0.001; 1.002 [1.001–1.004], p < 0.001; 1.002 [1.001–1.003], p < 0.001, respectively) and was a significant risk factor for high 24 h max Vasoactive inotropic score (Crude Odds Ratio [OR] [95% CI]: −0.015 [−0.022, −0.007], p < 0.001), serous effusion (Crude OR [95% CI]: 0.996 [0.992–0.999], p = 0.020), delayed sternal closure (Crude OR [95% CI]: 0.983 [0.971–0.996], p = 0.010), and the need for peritoneal dialysis (Crude OR [95% CI]: 0.988 [0.980–0.996], p = 0.005). The area under the ROC curve of PVI for delayed postoperative recovery was 0.722 (p < 0.001), and the estimated cutoff point was 300.3 mm2/m2.

Conclusion: PVI is a good predictor of early prognosis for surgical treatment of TOF patients.
Sphingosine 1-phosphate Stimulates Insulin Secretion and Improves Cell Survival by Blocking Voltage-dependent K+ Channels in β Cells
Authors: Liu Zhihong , Yang Huanhuan , Zhi Linping , Xue Huan , Lu Zhihong , Zhao Yanli , Cui Lijuan , Liu Tao , Ren Shouan , He Peifeng , Liu Yunfeng , Zhang Yi
Published: July 2021

Recent studies suggest that Sphingosine 1-phosphate (S1P) plays an important role in regulating glucose metabolism in type 2 diabetes. However, its effects and mechanisms of promoting insulin secretion remain largely unknown. Here, we found that S1P treatment decreased blood glucose level and increased insulin secretion in C57BL/6 mice. Our results further showed that S1P promoted insulin secretion in a glucose-dependent manner. This stimulatory effect of S1P appeared to be irrelevant to cyclic adenosine monophosphate signaling. Voltage-clamp recordings showed that S1P did not influence voltage-dependent Ca2+ channels, but significantly blocked voltage-dependent potassium (Kv) channels, which could be reversed by inhibition of phospholipase C (PLC) and protein kinase C (PKC). Calcium imaging revealed that S1P increased intracellular Ca2+ levels, mainly by promoting Ca2+ influx, rather than mobilizing intracellular Ca2+ stores. In addition, inhibition of PLC and PKC suppressed S1P-induced insulin secretion. Collectively, these results suggest that the effects of S1P on glucose-stimulated insulin secretion (GSIS) depend on the inhibition of Kv channels via the PLC/PKC signaling pathway in pancreatic β cells. Further, S1P improved β cell survival; this effect was also associated with Kv channel inhibition. This work thus provides new insights into the mechanisms whereby S1P regulates β cell function in diabetes.
Safety and Efficacy of Intravitreal Chemotherapy (Melphalan) to Treat Vitreous Seeds in Retinoblastoma
Authors: Yousef Yacoub A. , Al Jboor Mays , Mohammad Mona , Mehyar Mustafa , Toro Mario D. , Nazzal Rashed , Alzureikat Qusai H. , Rejdak Magdalena , Elfalah Mutasem , Sultan Iyad , Rejdak Robert , Al-Hussaini Maysa , Al-Nawaiseh Ibrahim
Published: July 2021

Background: Active vitreous seeds in eyes with retinoblastoma (Rb) adversely affects the treatment outcome. This study aimed to investigate the safety and efficacy of intravitreal melphalan chemotherapy (IViC) as a treatment for recurrent and refractory vitreous seeds in patients with Rb.

Methods: We used a retrospective non-comparative study of patients with intraocular Rb who had vitreous seeds and were treated by IViC (20–30 μg of melphalan) using the safety-enhanced anti-reflux technique. Tumor response, ocular toxicity, demographics, clinical features, and survival were analyzed.

Results: In total, 27 eyes were treated with 108 injections for recurrent (16 eyes) or refractory (11 eyes) vitreous seeds after failed systemic chemotherapy. A total of 15 (56%) were males, and 20 (74%) had bilateral disease. At diagnosis, the majority (n = 21) of the injected eyes were group D, and n = 6 were group C. Vitreous seeds showed complete regression in 21 (78%) eyes; 100% (n = 10) for eyes with focal seeds; 65% (n = 11/17 eyes) for eyes with diffuse seeds (p = 0.04); 7 (64%) eyes with refractory seeds; and 14 (87%) eyes with recurrent seeds showed complete response (p = 0.37). In total, 16 (59%) eyes developed side effects: retinal toxicity (48%), pupillary synechiae (15%), cataracts (30%), iris atrophy (7%), and retinal and optic atrophy (4%). Only one child was lost to follow-up whose family refused enucleation and none developed orbital tumor recurrence or distant metastasis.

Conclusion: IViC with melphalan is effective (more for focal than diffuse seeding) and a relatively safe treatment modality for Rb that can improve the outcomes of eye salvage procedures. However, unexpected toxicity can occur even with the standard dose of 20–30 μg.
Connectomics of Bone to Brain—Probing Physical Renderings of Cellular Experience
Authors: Knothe Tate Melissa L. , Srikantha Abhilash , Wojek Christian , Zeidler Dirk
Published: July 2021

“Brainless” cells, the living constituents inhabiting all biological materials, exhibit remarkably smart, i.e., stimuli-responsive and adaptive, behavior. The emergent spatial and temporal patterns of adaptation, observed as changes in cellular connectivity and tissue remodeling by cells, underpin neuroplasticity, muscle memory, immunological imprinting, and sentience itself, in diverse physiological systems from brain to bone. Connectomics addresses the direct connectivity of cells and cells’ adaptation to dynamic environments through manufacture of extracellular matrix, forming tissues and architectures comprising interacting organs and systems of organisms. There is imperative to understand the physical renderings of cellular experience throughout life, from the time of emergence, to growth, adaptation and aging-associated degeneration of tissues. Here we address this need through development of technological approaches that incorporate cross length scale (nm to m) structural data, acquired via multibeam scanning electron microscopy, with machine learning and information transfer using network modeling approaches. This pilot case study uses cutting edge imaging methods for nano- to meso-scale study of cellular inhabitants within human hip tissue resected during the normal course of hip replacement surgery. We discuss the technical approach and workflow and identify the resulting opportunities as well as pitfalls to avoid, delineating a path for cellular connectomics studies in diverse tissue/organ environments and their interactions within organisms and across species. Finally, we discuss the implications of the outlined approach for neuromechanics and the control of physical behavior and neuromuscular training.
Heterothermy as the Norm, Homeothermy as the Exception: Variable Torpor Patterns in the South American Marsupial Monito del Monte (Dromiciops gliroides)
Authors: Nespolo Roberto F. , Mejías Carlos , Espinoza Angelo , Quintero-Galvis Julián , Rezende Enrico L. , Fontúrbel Francisco E. , Bozinovic Francisco
Published: July 2021

Hibernation (i.e., multiday torpor) is considered an adaptive strategy of mammals to face seasonal environmental challenges such as food, cold, and/or water shortage. It has been considered functionally different from daily torpor, a physiological strategy to cope with unpredictable environments. However, recent studies have shown large variability in patterns of hibernation and daily torpor (“heterothermic responses”), especially in species from tropical and subtropical regions. The arboreal marsupial “monito del monte” (Dromiciops gliroides) is the last living representative of the order Microbiotheria and is known to express both short torpor episodes and also multiday torpor depending on environmental conditions. However, only limited laboratory experiments have documented these patterns in D. gliroides. Here, we combined laboratory and field experiments to characterize the heterothermic responses in this marsupial at extreme temperatures. We used intraperitoneal data loggers and simultaneous measurement of ambient and body temperatures (TA and TB, respectively) for analyzing variations in the thermal differential, in active and torpid animals. We also explored how this differential was affected by environmental variables (TA, natural photoperiod changes, food availability, and body mass changes), using mixed-effects generalized linear models. Our results suggest that: (1) individuals express short bouts of torpor, independently of TA and even during the reproductive period; (2) seasonal torpor also occurs in D. gliroides, with a maximum bout duration of 5 days and a mean defended TB of 3.6 ± 0.9°C (one individual controlled TB at 0.09°C, at sub-freezing TA); (3) the best model explaining torpor occurrence (Akaike information criteria weight = 0.59) discarded all predictor variables except for photoperiod and a photoperiod by food interaction. Altogether, these results confirm that this marsupial expresses a dynamic form of torpor that progresses from short torpor to hibernation as daylength shortens. These data add to a growing body of evidence characterizing tropical and sub-tropical heterothermy as a form of opportunistic torpor, expressed as daily or seasonal torpor depending on environmental conditions.
Pathogen-Mediated Stomatal Opening: A Previously Overlooked Pathogenicity Strategy in the Oomycete Pathogen Phytophthora infestans
Authors: Yang Li-Na , Liu Hao , Wang Yan-Ping , Seematti Jenifer , Grenville-Briggs Laura J. , Wang Zonghua , Zhan Jiasui
Published: July 2021

Phytophthora infestans, the most damaging oomycete pathogen of potato, is specialized to grow sporangiophore through opened stomata for secondary inoculum production. However, it is still unclear which metabolic pathways in potato are manipulated by P. infestans in the guard cell–pathogen interactions to open the stomata. Here microscopic observations and cell biology were used to investigate antagonistic interactions between guard cells and the oomycete pathogen. We observed that the antagonistic interactions started at the very beginning of infection. Stomatal movement is an important part of the immune response of potato to P. infestans infection and this occurs through guard cell death and stomatal closure. We observed that P. infestans appeared to manipulate metabolic processes in guard cells, such as triacylglycerol (TAG) breakdown, starch degradation, H2O2 scavenging, and NO catabolism, which are involved in stomatal movement, to evade these stomatal defense responses. The signal transduction pathway of P. infestans-induced stomatal opening likely starts from H2O2 and NO scavenging, along with TAG breakdown while the subsequent starch degradation reinforces the opening process by strengthening guard cell turgor and opening the stomata to their maximum aperture. These results suggest that stomata are a barrier stopping P. infestans from completing its life cycle, but this host defense system can be bypassed through the manipulation of diverse metabolic pathways that may be induced by P. infestans effector proteins.
Field-Grown Rice Plants Become More Productive When Exposed to Artificially Damaged Weed Volatiles at the Seedling Stage
Authors: Shiojiri Kaori , Ozawa Rika , Uefune Masayoshi , Takabayashi Junji
Published: July 2021

It is known that undamaged plants that have been exposed to volatiles from damaged con- or heterospecific plants become more resistant against herbivores. This is one of the plants’ induced resistant responses against herbivores. To test whether this response can be used for rice production, we conducted the following experiments over 2 years (2012 and 2013). Rice seedlings were first planted in the rice seedling bed for 2 weeks in early May. There, half of the rice seedlings were exposed to artificially damaged weed volatiles three times for 12 days (treated plants). Weeds were randomly collected from the areas that were >100 m away from the seedling bed and the rice paddy fields. The remaining seedlings were not exposed (control plants). In the middle of May, bunches (ca. three seedlings per bunch) were transplanted to the rice paddy field. In July, leaf damage was observed. The total number of leaves in the treated and control plants was not significantly different. In contrast, the total number of damaged leaves in the treated plants was significantly lower than that in the control plants. In September, rice grains were harvested. The average weight of a rice grain from the treated and control plants was not significantly different. However, the weight of grains per bunch of treated plants was significantly higher than that of control plants; this indicated a significant increase of the number of grains by 23% in 2012 and by 18% in 2013 in the treated plants compared to that in the control plants. The volatiles emitted from the weeds included monoterpenoids (40.4% in total), green leaf volatiles (46.5%), short-chain alcohols (5.3%), short-chain ketone (5.4%), short-chain acetate (0.5%), short-chain aldehyde (1.1%), and hydrocarbon (0.7%). These results suggest that exposure of volatiles from artificially damaged weeds to rice seedlings has the potential to increase rice production.
SNP Alleles Associated With Low Bolting Tendency in Sugar Beet
Authors: Ravi Samathmika , Campagna Giovanni , Della Lucia Maria Cristina , Broccanello Chiara , Bertoldo Giovanni , Chiodi Claudia , Maretto Laura , Moro Matteo , Eslami Azam Sadat , Srinivasan Subhashini , Squartini Andrea , Concheri Giuseppe , Stevanato Piergiorgio
Published: July 2021

The identification of efficient molecular markers related to low bolting tendency is a priority in sugar beet (Beta vulgaris L.) breeding. This study aimed to identify SNP markers associated with low bolting tendency by establishing a genome-wide association study. An elaborate 3-year field trial comprising 13 sugar beet lines identified L14 as the one exhibiting the lowest bolting tendency along with an increased survival rate after autumnal sowing. For SNP discovery following phenotyping, contrasting phenotypes of 24 non-bolting and 15 bolting plants of the L14 line were sequenced by restriction site-associated DNA sequencing (RAD-seq). An association model was established with a set of 10,924 RAD-based single nucleotide polymorphism (SNP) markers. The allelic status of the most significantly associated SNPs ranked based on their differential allelic status between contrasting phenotypes (p < 0.01) was confirmed on three different validation datasets comprising diverse sugar beet lines and varieties adopting a range of SNP detection technologies. This study has led to the identification of SNP_36780842 and SNP_48607347 linked to low bolting tendency and can be used for marker-assisted breeding and selection in sugar beet.
Building Resilience During COVID-19: Recommendations for Adapting the DREAM Program – Live Edition to an Online-Live Hybrid Model for In-Person and Virtual Classrooms
Authors: Parrott Julia , Armstrong Laura L. , Watt Emmalyne , Fabes Robert , Timlin Breanna
Published: July 2021

In standard times, approximately 20% of children and youth experience significant emotional, behavioral, or social challenges. During COVID-19, however, over half of parents have reported mental health symptoms in their children. Specifically, depressive symptoms, anxiety, contamination obsessions, family well-being challenges, and behavioral concerns have emerged globally for children during the pandemic. Without treatment or prevention, such concerns may hinder positive development, personal life trajectory, academic success, and inhibit children from meeting their potential. A school-based resiliency program for children (DREAM) for children was developed, and the goal of this study was to collaborate with stakeholders to translate it into an online-live hybrid. Our team developed a methodology to do this based on Knowledge Translation-Integration (KTI), which incorporates stakeholder engagement throughout the entire research to action process. KTI aims to ensure that programs are acceptable, sustainable, feasible, and credible. Through collaboration with parents and school board members, qualitative themes of concerns, recommendations and validation were established, aiding in meaningful online-live translation. Even though the original program was developed for intellectually gifted children, who are at greater risk for mental health concerns, stakeholders suggested using the program for both gifted and non-gifted children, given the universal applicability of the tools, particularly during this pandemic time period when mental health promotion is most relevant. An online-live approach would allow students studying at home and those studying in the classroom to participate in the program. Broader implications of this study include critical recommendations for the development of both online-live school programs in general, as well as social-emotional literacy programs for children.
Testing Effects of Foreign Language Listening Anxiety on Chinese University Students' English Listening Test Performance
Authors: Liu Meihua , Xu Hongliang
Published: July 2021

The present research explored how foreign language listening anxiety (FLLA) affected Chinese university students' English listening test performance and how proficiency and gender mediated the effects of FLLA on the latter. Two different populations from two universities in China answered the 20-item Foreign Language Listening Anxiety Scale (FLLAS) as well as a demographic questionnaire and took an English listening test. Analyses of the collected data revealed the following major findings: (a) Five latent factors underlay the FLLAS, (b) when working alone, FLLA significantly negatively predicted students' English listening test performance, and (c) when working with proficiency and gender, English proficiency level, gender and FLLAS2 (proficiency in English listening) significantly predicted students' English listening test performance. These findings confirm the negative effects of FLLA on students' English listening test performance. They also indicate that English proficiency and gender mediate FLLA's effects on the latter, with English proficiency not only directly but also indirectly affecting the latter.
Shared Decision Making in Primary Care Based Depression Treatment: Communication and Decision-Making Preferences Among an Underserved Patient Population
Authors: Matthews Elizabeth B. , Savoy Margot , Paranjape Anuradha , Washington Diana , Hackney Treanna , Galis Danielle , Zisman-Ilani Yaara
Published: July 2021

Objectives: Although depression is a significant public health issue, many individuals experiencing depressive symptoms are not effectively linked to treatment by their primary care provider, with underserved populations have disproportionately lower rates of engagement in depression care. Shared decision making (SDM) is an evidence-based health communication framework that can improve collaboration and optimize treatment for patients, but there is much unknown about how to translate SDM into primary care depression treatment among underserved communities. This study seeks to explore patients' experiences of SDM, and articulate communication and decision-making preferences among an underserved patient population receiving depression treatment in an urban, safety net primary care clinic.

Methods: Twenty-seven patients with a depressive disorder completed a brief, quantitative survey and an in-depth semi-structured interview. Surveys measured patient demographics and their subjective experience of SDM. Qualitative interview probed for patients' communication preferences, including ideal decision-making processes around depression care. Interviews were transcribed verbatim and analyzed using thematic analysis. Univariate statistics report quantitative findings.

Results: Overall qualitative and quantitative findings indicate high levels of SDM. Stigma related to depression negatively affected patients' initial attitude toward seeking treatment, and underscored the importance of patient-provider rapport. In terms of communication and decision-making preferences, patients preferred collaboration with doctors during the information sharing process, but desired control over the final, decisional outcome. Trust between patients and providers emerged as a critical precondition to effective SDM. Respondents highlighted several provider behaviors that helped facilitated such an optimal environment for SDM to occur.

Conclusion: Underserved patients with depression preferred taking an active role in their depression care, but looked for providers as partner in this process. Due to the stigma of depression, effective SDM first requires primary care providers to ensure that they have created a safe and trusting environment where patients are able to discuss their depression openly.
Robot-Assisted Image-Guided Interventions
Authors: Unger Michael , Berger Johann , Melzer Andreas
Published: July 2021

Image guidance is a common methodology of minimally invasive procedures. Depending on the type of intervention, various imaging modalities are available. Common imaging modalities are computed tomography, magnetic resonance tomography, and ultrasound. Robotic systems have been developed to enable and improve the procedures using these imaging techniques. Spatial and technological constraints limit the development of versatile robotic systems. This paper offers a brief overview of the developments of robotic systems for image-guided interventions since 2015 and includes samples of our current research in this field.
Is There an Association Between Fixed Orthodontic Treatment and Initiation of Eating Disorders? A Review of Currently Available Evidence
Authors: Koukou Melina , Javed Fawad , Michelogiannakis Dimitrios
Published: July 2021

Objectives: The aim was to review the available literature regarding the potential association between fixed orthodontic treatment (OT) and the onset of eating disorders (EDs).

Method and Materials: Six indexed databases were searched until November 2020. The inclusion criteria were as follows: (a) patients undergoing fixed OT and (b) EDs in relation to fixed OT. Commentaries, letters to the Editor, reviews, and studies in patients with EDs not undergoing fixed OT were excluded. The pattern of the present review was customized to summarize the pertinent information.

Results: Four out of 10,076 initially-identified studies were included, and all of them were case reports. All patients were females, and the EDs reported were either anorexia nervosa (AN) or bulimia nervosa (BN). In three case reports, patients developed EDs after the initiation of OT. Fixed OT was performed in all the studies, and a variety of oral complications such as sore mouth, gingivitis, tooth surface demineralization, and others were reported.

Conclusion: Based upon the limited available evidence, the association between OT and the onset of EDs remains unclear. Further well-designed observational clinical studies are needed in this regard.