bluuebunny/crossref_metadata_2025 huggingface dataset:
Disparate kinetics of change in responses to electrical stimulation at the thoracic and lumbar level during fatiguing isometric knee extension
Authors: Brownstein Callum G. , Souron Robin , Royer Nicolas , Singh Benjamin , Lapole Thomas , Millet Guillaume Y.
Published: November 2019

The present study compared the fatigue-induced change of matched-amplitude thoracic evoked potential (TMEP) and lumbar evoked potential (LEP) following electrical stimulation. Ten participants performed a 3 × 3 min isometric knee extension contraction separated by 4 min of recovery at the level of EMG required to produce 50% maximal voluntary contraction (MVC) force at baseline. The TMEP and LEP were evoked during the ongoing contraction at baseline and every minute into the fatiguing protocol and during recovery. Both responses were also assessed during a transcranial magnetic stimulation (TMS) evoked silent period to elicit a TMS-TMEP and TMS-LEP to assess responses without the confounding influence of descending drive. The results displayed disparate kinetics of the TMS-TMEP and TMS-LEP throughout the fatiguing protocol. The TMS-TMEP was reduced at all time points during exercise ( P < 0.001), whereas the TMS-LEP was reduced at 2 min into set 1 and 1 min into sets 2 and 3 ( P ≤ 0.04). TMS-LEPs were higher than the TMS-TMEPs at most time points ( P ≤ 0.04). No change was observed in the TMEP or LEP. When evoked during the silent period, the reduction in TMEP is greater than the LEP during fatiguing isometric exercise. The disparate kinetics of change suggest that differential mechanisms are responsible for evoked responses to thoracic and lumbar stimulation. More research is required to identify the mechanisms responsible for the TMEP and LEP before precise inferences can be made on what fatigue-induced changes in these variables reflect.

NEW & NOTEWORTHY Assessing spinal excitability using lumbar stimulation when measuring responses in lower limbs has been suggested as an alternative method that could circumvent the issues associated with thoracic stimulation. The present study compared responses to the two types of stimuli throughout a fatiguing protocol and demonstrated that lumbar evoked responses differ substantially from thoracic responses when measured in the absence of voluntary drive. These findings suggest that different mechanisms are responsible for evoked responses to thoracic and lumbar stimuli.
Stiffness Sensing by Cells
Authors: Janmey Paul A. , Fletcher Daniel A. , Reinhart-King Cynthia A.
Published: November 2019

Physical stimuli are essential for the function of eukaryotic cells, and changes in physical signals are important elements in normal tissue development as well as in disease initiation and progression. The complexity of physical stimuli and the cellular signals they initiate are as complex as those triggered by chemical signals. One of the most important, and the focus of this review, is the effect of substrate mechanical properties on cell structure and function. The past decade has produced a nearly exponentially increasing number of mechanobiological studies to define how substrate stiffness alters cell biology using both purified systems and intact tissues. Here we attempt to identify common features of mechanosensing in different systems while also highlighting the numerous informative exceptions to what in early studies appeared to be simple rules by which cells respond to mechanical stresses.
Impact of a Tailored Nutrition and Lifestyle Intervention for Overweight Cancer Survivors on Dietary Patterns, Physical Activity, Quality of Life, and Cardiometabolic Profiles
Authors: Spees Colleen K. , Braun Ashlea C. , Hill Emily B. , Grainger Elizabeth M. , Portner James , Young Gregory S. , Kleinhenz Matthew D. , Chitchumroonchokchai Chureeporn , Clinton Steven K.
Published: November 2019

Survivors of cancer often experience treatment-related toxicity in addition to being at risk of cancer recurrence, second primary cancers, and greater all-cause mortality. The objective of this study was to test the safety and efficacy of an intensive evidence-based garden intervention to improve outcomes for cancer survivors after curative therapy. To do so, a clinical trial of adult overweight and obese cancer survivors within 2 years of completing curative therapy was completed. The 6-month intervention, delivered within the context of harvesting at an urban garden, combined group education with cooking demonstrations, remote motivational interviewing, and online digital resources. Data on dietary patterns, program satisfaction, and quality of life were collected via questionnaires; anthropometrics, physical activity, and clinical biomarkers were measured objectively. Of the 29 participants, 86% were white, 83% were female, and the mean age was 58 years. Compared to baseline, participants had significant improvements in Healthy Eating Index (HEI) scores (+5.2 points, p=0.006), physical activity (+1,208 steps, p=0.033), and quality of life (+16.07 points, p=0.004). Significant improvements were also documented in weight (−3.9 kg), waist circumference (−5.5 cm), BMI (−1.5 kg/m2), systolic BP (−9.5 mmHg), plasma carotenoids (+35%), total cholesterol (−6%), triglycerides (−14%), hs-CRP (−28%), and IGFBP-3 (−5%) (all p<0.010). These findings demonstrate a tailored multifaceted garden-based biobehavioral intervention for overweight and obese cancer survivors after curative therapy is safe and highly effective, warranting larger randomized controlled trials to identify program benefits, optimal maintenance strategies, program value relative to cost, and approaches for integration into a survivor’s oncology management program. This trial is registered on ClinicalTrials.gov NCT02268188.
Artemether Activation of AMPK/GSK3β(ser9)/Nrf2 Signaling Confers Neuroprotection towards β-Amyloid-Induced Neurotoxicity in 3xTg Alzheimer’s Mouse Model
Authors: Li Shuai , Zhao Xia , Lazarovici Philip , Zheng Wenhua
Published: November 2019

Alzheimer’s disease is a severe neurodegenerative disease. Multiple factors involving neurofibrillary tangles and amyloid-β plaques lead to the progression of the AD, generated by aggregated hyperphosphorylated Tau protein. Inflammation, mitochondrial dysfunction, and oxidative stress play a significant role in the progression of AD. It has been therefore suggested that the multifactorial nature of AD pathogenesis requires the design of antioxidant drugs with a broad spectrum of neuroprotective activities. For this reason, the use of natural products, characterized by multiple pharmacological properties is advantageous as AD-modifying drugs over the single-targeted chemicals. Artemether, a peroxide sesquiterpenoid lipid-soluble compound, has been used in the clinic as an antimalarial drug. Also, it exhibits potent anti-inflammatory and antioxidant activities. Here, we report the neuroprotective effects of Artemether towards Aβ-induced neurotoxicity in neuronal cell cultures. A temporal correlation was found between Artemether neuroprotection towards Aβ-induced neurotoxicity and AMPK/GSK3β phosphorylation activity and increased expression of the activated Nrf2 signaling pathway. In 3xTg-AD mice, Artemether attenuated learning and memory deficits, inhibited cortical neuronal apoptosis and glial activation, inhibited oxidative stress through decrease of lipid peroxidation and increased expression of SOD, and reduced Aβ deposition and tau protein phosphorylation. Moreover, in 3xTg-AD mice, Artemether induced phosphorylation of the AMPK/GSK3β pathway which activated Nrf2, increasing the level of antioxidant protein HO-1. These activities probably produced the antioxidant and anti-inflammatory effects responsible for the neuroprotective effects of Artemether in the 3xTg-AD mouse model. These findings propose Artemether as a new drug for the treatment of AD disease.
The Prognostic Value of the Expression of SMC4 mRNA in Breast Cancer
Authors: Ma Rui-min , Yang Fan , Huang Du-ping , Zheng Min , Wang Yi-luan
Published: November 2019

Aim. To investigate the mRNA expression and clinical significance of structural maintenance of chromosomes protein 4 (SMC4) in breast cancer. Methods. A total of 23 paired samples were sequenced, and data from the Cancer Genome Atlas were analyzed. Results. SMC4 mRNA level was significantly upregulated in breast cancer tissues (P<0.001). Patients with high mRNA expression of SMC4 had significantly poor survival (P=0.012). Subgroup analyses show that in nontriple negative breast cancer (non-TNBC) patients, the high SMC4 mRNA expression, older age (>65), negative progesterone receptor, and advanced stages (III-IV) were independent risk factors (HR=3.293, 95% CI 1.257-8.625, P=0.015). In patients with TNBC, high mRNA expression of SMC4 correlated with better survival rate (P<0.046). Conclusion. SMC4 mRNA level is a good prognostic biomarker for patients with breast cancer.
Synthesis and Characterization of a New Collagen-Alginate Aerogel for Tissue Engineering
Authors: Muñoz-Ruíz Abraham , Escobar-García Diana M. , Quintana Mildred , Pozos-Guillén Amaury , Flores Héctor
Published: November 2019

Scaffolds have been used as extracellular matrix analogs to promote cell migration, cell attachment, and cell proliferation. The use of aerogels and carbon-based nanomaterials has recently been proposed for tissue engineering due to their properties. The aim of this study is to develop a highly porous collagen-alginate(-graphene oxide) aerogel-based scaffold. The GO synthesis was performed by Hummers method; a collagen-alginate and collagen-alginate-GO hydrogel were synthetized; then, they were treated by a supercritical drying process. The aerogels obtained were evaluated by SEM and FTIR. Osteoblasts were seeded over the scaffolds and evaluated by SEM. According to the characterization, the aerogels showed a highly porous interconnected network covered by a nonporous external wall. According to the FTIR, the chemical functional groups of collagen and GO were maintained after the supercritical process. The SEM images after cell culture showed that a collagen-alginate scaffold promotes cell attachment and proliferation. The alginate-collagen aerogel-based scaffold could be a platform for tissue engineering since it shows adequate properties. Further studies are needed to determine the cell interactions with GO.
Roles of Achieved Levels of Low-Density Lipoprotein Cholesterol and High-Sensitivity C-Reactive Protein on Cardiovascular Outcome in Statin Therapy
Authors: Hyun Myung Han , Lee Yuchang , Choi Byoung Geol , Na Jin Oh , Choi Cheol Ung , Kim Jin Won , Kim Eung Ju , Rha Seung-Woon , Park Chang Gyu , Lee Eunmi , Seo Hong Seog
Published: November 2019

In statin therapy, the prognostic role of achieved low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP) in cardiovascular outcomes has not been fully elucidated. A total of 4,803 percutaneous coronary intervention (PCI)-naïve patients who prescribed moderate intensity of statin therapy were followed up. Total and each component of major adverse cardiovascular events (MACE) according to LDL-C and hsCRP quartiles were compared. The incidence of 5-year total MACEs in the highest quartile group according to the followed-up hsCRP was higher than that in the lowest quartile (hazard ratio (HR) = 2.16, p<0.001). However, there was no difference between the highest and lowest quartiles of the achieved LDL-C (HR = 0.95, p=0.743). After adjustment of potential confounders, the incidence of total death, de novo PCI, atrial fibrillation, and heart failure in the highest quartile of followed-up hsCRP, was higher than that in the lowest quartile (all p<0.05). However, other components except for de novo PCI in the highest quartile by achieved LDL-C was not different to that in the lowest quartile. These results suggest that followed-up hsCRP can be more useful for predicting future cardiovascular outcome than achieved LDL-C in PCI-naïve patients with statin therapy.
PTPN21 Overexpression Promotes Osteogenic and Adipogenic Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells but Inhibits the Immunosuppressive Function
Authors: Wang Huafang , Ye Xiaohang , Xiao Haowen , Zhu Ni , Wei Cong , Sun Xiang , Wang Limengmeng , Wang Binsheng , Yu Xiaohong , Lai Xiaoyu , Fu Shan , Huang He
Published: November 2019

Protein tyrosine phosphatases (PTPs) act as key regulators in various cellular processes such as proliferation, differentiation, and migration. Our previous research demonstrated that non-receptor-typed PTP21 (PTPN21), a member of the PTP family, played a critical role in the proliferation, cell cycle, and chemosensitivity of acute lymphoblastic leukemia cells. However, the role of PTPN21 in the bone marrow microenvironment has not yet been elucidated. In the study, we explored the effects of PTPN21 on human bone marrow-derived mesenchymal stem cells (BM-MSCs) via lentiviral-mediated overexpression and knock-down of PTPN21 in vitro. Overexpressing PTPN21 in BM-MSCs inhibited the proliferation through arresting cell cycle at the G0phase but rendered them a higher osteogenic and adipogenic differentiation potential. In addition, overexpressing PTPN21 in BM-MSCs increased their senescence levels through upregulation of P21 and P53 and dramatically changed the levels of crosstalk with their typical target cells including immunocytes, tumor cells, and vascular endothelial cells. BM-MSCs overexpressing PTPN21 had an impaired immunosuppressive function and an increased capacity of recruiting tumor cells and vascular endothelial cells in a chemotaxis transwell coculture system. Collectively, our data suggested that PTPN21 acted as a pleiotropic factor in modulating the function of human BM-MSCs.
The Efficacy of Functional and Traditional Exercise on the Body Composition and Determinants of Physical Fitness of Older Women: A Randomized Crossover Trial
Authors: Resende-Neto Antônio Gomes de , Aragão-Santos José Carlos , Oliveira-Andrade Bruna Caroline , Silva Vasconcelos Alan Bruno , De Sá Clodoaldo Antônio , Aidar Felipe José , DeSantana Josimari Melo , Cadore Eduardo Lusa , Da Silva-Grigoletto Marzo Edir
Published: November 2019

Aim. To analyze the efficacy of functional training (FT) and traditional training (TT) in body composition and determinants of physical fitness in older women. Methods. This is a randomized clinical trial in which participants performed two 12-week periods of different training methods, separated by eight weeks of washout. Forty-eight physically active older women (≥60 years of age) completed the intervention in three groups: (i) program that started with FT and ended with TT (FT ⟶ TT: n = 19), (ii) program that started with TT and ended with FT (TT ⟶ FT: n = 13), and (iii) stretching group (SG: n = 16). Before and after the interventions, the body composition was evaluated by bioimpedance, the physical fitness by battery of the Senior Fitness Test, and the quality of movement by Functional Movement Screen®. Results. Compared with SG, TT ⟶ FT and FT ⟶ TT promoted significant improvements in balance/agility (13.60 and 13.06%, respectively) and upper limb strength (24.91 and 16.18%). Only FT showed a statistically significant improvement in the strength of the lower limbs, cardiorespiratory capacity, and movement patterns when compared with SG considering the adaptations of methods separately. Conclusion. The programs used are equally effective in increasing physical fitness for daily activities in physically active older women, and therefore, they may be complementary to combat some of the deleterious effects of senescence.
Heme Oxygenases: Cellular Multifunctional and Protective Molecules against UV-Induced Oxidative Stress
Authors: Chen ShiDa , Wang XiaoYu , Nisar Muhammad Farrukh , Lin Mao , Zhong Julia Li
Published: November 2019

Ultraviolet (UV) irradiation can be considered as a double-edged sword: not only is it a crucial environmental factor that can cause skin-related disorders but it can also be used for phototherapy of skin diseases. Inducible heme oxygenase-1 (HO-1) in response to a variety of stimuli, including UV exposure, is vital to maintain cell homeostasis. Heme oxygenase-2 (HO-2), another member of the heme oxygenase family, is constitutively expressed. In this review, we discuss how heme oxygenase (HO), a vital rate-limiting enzyme, participates in heme catabolism and cytoprotection. Phylogenetic analysis showed that there may exist a functional differentiation between HO-1 and HO-2 during evolution. Furthermore, depending on functions in immunomodulation and antioxidation, HO-1 participates in disease progression, especially in pathogenesis of skin diseases, such as vitiligo and psoriasis. To further investigate the particular role of HO-1 in diseases, we summarized the profile of the HO enzyme system and its related signaling pathways, such as Nrf2 and endoplasmic reticulum crucial signaling, both known to regulate HO-1 expression. Furthermore, we report on a C-terminal truncation of HO-1, which is generally considered as a signal molecule. Also, a newly identified alternative splice isoform of HO-1 not only provides us a novel perspective on comprehensive HO-1 alternative splicing but also offers us a basis to clarify the relationship between HO-1 transcripts and oxidative diseases. To conclude, the HO system is not only involved in heme catabolism but also involved in biological processes related to the pathogenesis of certain diseases, even though the mechanism of disease progression still remains sketchy. Further understanding the role of the HO system and its relationship to UV is helpful for revealing the HO-related signaling networks and the pathogenesis of many diseases.
Combined Economic and Emission Dispatch Problem of Wind‐Thermal Power System Using Gravitational Particle Swarm Optimization Algorithm
Authors: Jiang Shanhe , Zhang Chaolong , Wu Wenjin , Chen Shijun
Published: November 2019

In this paper, a novel hybrid optimization approach, namely, gravitational particle swarm optimization algorithm (GPSOA), is introduced based on particle swarm optimization (PSO) and gravitational search algorithm (GSA) to solve combined economic and emission dispatch (CEED) problem considering wind power availability for the wind‐thermal power system. The proposed algorithm shows an interesting hybrid strategy and perfectly integrates the collective behaviors of PSO with the Newtonian gravitation laws of GSA. GPSOA updates particle’s velocity caused by the dependent random cooperation of GSA gravitational acceleration and PSO velocity. To describe the stochastic characteristics of wind speed and output power, Weibull‐based probability density function (PDF) is utilized. The CEED model employed consists of the fuel cost objective and emission‐level target produced by conventional thermal generators and the operational cost generated by wind turbines. The effectiveness of the suggested GPSOA is tested on the conventional thermal generator system and the modified wind‐thermal power system. Results of GPSOA‐based CEED problems by means of the optimal fuel cost, emission value, and best compromise solution are compared with the original PSO, GSA, and other state‐of‐the‐art optimization approaches to reveal that the introduced GPSOA exhibits competitive performance improvements in finding lower fuel cost and emission cost and best compromise solution.
Activation of TGR5 Partially Alleviates High Glucose-Induced Cardiomyocyte Injury by Inhibition of Inflammatory Responses and Oxidative Stress
Authors: Deng Li , Chen Xuxin , Zhong Yi , Wen Xing , Cai Ying , Li Jiafu , Fan Zhongcai , Feng Jian
Published: November 2019

High glucose- (HG-) induced cardiomyocyte injury is the leading cause of diabetic cardiomyopathy, which is associated with the induction of inflammatory responses and oxidative stress. TGR5 plays an important role in the regulation of glucose metabolism. However, whether TGR5 has cardioprotective effects against HG-induced cardiomyocyte injury is unknown. Neonatal mouse cardiomyocytes were isolated and incubated in a HG medium. Protein and mRNA expression was detected by western blotting and RT-PCR, respectively. Cell apoptosis was determined by Hoechst 33342 staining and flow cytometry. After treatment of cells with HG, TGR5-selective agonist INT-777 reduced the increase in expression of proinflammatory cytokines and NF-κB, whereas pretreatment of cells with TGR5 shRNA significantly reduced the inhibitory effects of INT-777. We also found that INT-777 increased the protein expression of Nrf2 and HO-1. In the presence of TGR5 shRNA, the expression of Nrf2 and HO-1 was reduced, indicating that TGR5 may exert an antioxidant effect partially through the Nrf2/HO-1 pathway. Furthermore, INT-777 treatment inhibited HG-induced ROS production and apoptosis that were attenuated in the presence of TGR5 shRNA or ZnPP (HO-1 inhibitor). Activation of TGR5 has cardioprotective effects against HG-induced cardiomyocyte injury and could be a pharmacological target for the treatment of diabetic cardiomyopathy.
Stochastic Dynamic Model of Sulfate Corrosion Reactions in Concrete Materials considering the Effects of Colored Gaussian Noises
Authors: Li Tao , Zhang Bin
Published: November 2019

The corrosion reactions in concrete materials subjected to external environment attack can lead to the deterioration of concrete. However, the effects of internal fluctuations on the corrosion reaction process have not been reported in current studies on damage of concrete materials. To comprehensively describe the effects of internal fluctuations, the stochastic dynamic model of corrosion reactions in concrete materials subjected to sulfate attack is established based on the law of mass conservation and random process theory, in which internal fluctuations and the parameters of the chemical system are, respectively, regarded as colored Gaussian noises and a series of random variables. An experiment of sulfate corrosion reactions in concrete material is carried out to verify the effectiveness of the proposed method. Furthermore, the effects of variations of the initial reactant concentrations on the concentration evolution processes of the corrosion products are investigated. Results show that the stochastic dynamical responses of the corrosion reactions in concrete can be comprehensively investigated by the proposed stochastic mathematical model; the probabilistic information of the corrosion products can also be obtained conveniently. The concentration evolution process of sulfate corrosion products is a random process. The experimental data are only some samples of the random process. Concentrations of the corrosion products in concrete materials significantly fluctuate with the variations of the initial reactant concentrations.
Therapeutic Approaches for Peripheral and Central Neuropathic Pain
Authors: Szok Délia , Tajti János , Nyári Aliz , Vécsei László , Trojano Luigi
Published: November 2019

Neuropathic pain is a chronic secondary pain condition, which is a consequence of peripheral or central nervous (somatosensory) system lesions or diseases. It is a devastating condition, which affects around 7% of the general population. Numerous etiological factors contribute to the development of chronic neuropathic pain. It can originate from the peripheral part of the nervous system such as in the case of trigeminal or postherpetic neuralgia, peripheral nerve injury, painful polyneuropathies, or radiculopathies. Central chronic neuropathic pain can develop as a result of spinal cord or brain injury, stroke, or multiple sclerosis. As first-line pharmacological treatment options, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and gabapentinoids are recommended. In trigeminal neuralgia, carbamazepine and oxcarbazepine are the first-choice drugs. In drug-refractory cases, interventional, physical, and psychological therapies are available. This review was structured based on a PubMed search of papers published in the field from 2010 until May 2019.
Quality Assessment of Systematic Review of the Bariatric Surgery for Diabetes Mellitus
Authors: Jin Xinye , Wang Jinjing , Li Xueqiong , An Ping , Wang Haibin , Mao Wenfeng , Zhou Qi , Chen Yaolong , Wang Jie , Chen Kang , Mu Yiming
Published: November 2019

Objective. Using the AMSTAR tool, this study evaluated the quality of systematic reviews (SRs) that assessed the efficacy of bariatric surgery in diabetic patients. We aimed to identify studies that can be used as clinical references. Methods. Medline (via PubMed), EMBASE, Epistemonikos, Web of Science, Cochrane Library, CBM, CNKI, and Wanfang Data were systematically searched from inception to December 31, 2017. Two reviewers independently selected SRs and extracted data. Disagreements were solved by discussions or through consultation with a third reviewer. Reviewers extracted data (characteristics of included SRs, e.g., publication year, language, and number of authors) into the predefined tables in the Microsoft Excel 2013 sheet. Data were visualized using the forest plot in RevMan 5.3 software. Results. A total of 64 SRs were included. The average AMSTAR score was 7.4±1.7. AMSTAR scores of 7 (n=21, 32.8%) and 8 (n=14, 28.1%) were most common. The AMSTAR scores of SRs published before 2016 (n=46, 71.9%) were compared with SRs published after 2016 (n=18, 28.1%), and no significant differences were observed (MD=−0.79, 95% confidence interval (CI) -1.65-0.07, P=0.07). For SRs published in Chinese (n=17, 26.6%) compared to those published in English (n=47, 73.4%), the AMSTAR scores significantly differed (MD=0.21, 95% CI (-0.55, 0.97), P=0.59). For SRs published in China (n=33, 51.6%) compared to those published outside of China (n=31, 48.4%), significant differences in the AMSTAR scores were observed (MD=1.10, 95% CI (0.29, 1.91), P=0.008). For SRs with an author number≤6 (n=31, 48.4%) compared to SRs with authors≥6 (n=33, 51.6%), no significant differences were observed (MD=−0.36, 95% CI (-1.22, 0.50), P=0.41). For high-quality SRs published after 2016 (n=11, 17.2%) compared to other SRs (n=53, 82.8%), statistically significant differences were noted (MD=1.75, 95% CI (1.01, 2.49), P<0.00001). Conclusions. The number of SRs assessing the efficacy of bariatric surgery in diabetic patients is increasing by year, but only a small number meet the criteria to support guideline recommendations. Study protocols not being registered, grey literature not retrieved, incorporation of grey literature as exclusion criteria, and failure to evaluate publication bias and report a conflict of interest were the main causes of low AMSTAR scores.
Active Set Type Algorithms for Nonnegative Matrix Factorization in Hyperspectral Unmixing
Authors: Sun Li , Han Congying , Liu Ziwen
Published: November 2019

Hyperspectral unmixing is a powerful method of the remote sensing image mining that identifies the constituent materials and estimates the corresponding fractions from the mixture. We consider the application of nonnegative matrix factorization (NMF) for the mining and analysis of spectral data. In this paper, we develop two effective active set type NMF algorithms for hyperspectral unmixing. Because the factor matrices used in unmixing have sparse features, the active set strategy helps reduce the computational cost. These active set type algorithms for NMF is based on an alternating nonnegative constrained least squares (ANLS) and achieve a quadratic convergence rate under the reasonable assumptions. Finally, numerical tests demonstrate that these algorithms work well and that the function values decrease faster than those obtained with other algorithms.
Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non–Small Cell Lung Cancer
Authors: Zhang Jiajia , Ji Zhicheng , Caushi Justina X. , El Asmar Margueritta , Anagnostou Valsamo , Cottrell Tricia R. , Chan Hok Yee , Suri Prerna , Guo Haidan , Merghoub Taha , Chaft Jamie E. , Reuss Joshua E. , Tam Ada J. , Blosser Richard L. , Abu-Akeel Mohsen , Sidhom John-William , Zhao Ni , Ha Jinny S. , Jones David R. , Marrone Kristen A. , Naidoo Jarushka , Gabrielson Edward , Taube Janis M. , Velculescu Victor E. , Brahmer Julie R. , Housseau Franck , Hellmann Matthew D. , Forde Patrick M. , Pardoll Drew M. , Ji Hongkai , Smith Kellie N.
Published: November 2019

Purpose:

Neoadjuvant PD-1 blockade is a promising treatment for resectable non–small cell lung cancer (NSCLC), yet immunologic mechanisms contributing to tumor regression and biomarkers of response are unknown. Using paired tumor/blood samples from a phase II clinical trial (NCT02259621), we explored whether the peripheral T-cell clonotypic dynamics can serve as a biomarker for response to neoadjuvant PD-1 blockade.

Experimental Design:

T-cell receptor (TCR) sequencing was performed on serial peripheral blood, tumor, and normal lung samples from resectable NSCLC patients treated with neoadjuvant PD-1 blockade. We explored the temporal dynamics of the T-cell repertoire in the peripheral and tumoral compartments in response to neoadjuvant PD-1 blockade by using the TCR as a molecular barcode.

Results:

Higher intratumoral TCR clonality was associated with reduced percent residual tumor at the time of surgery, and the TCR repertoire of tumors with major pathologic response (MPR; <10% residual tumor after neoadjuvant therapy) had a higher clonality and greater sharing of tumor-infiltrating clonotypes with the peripheral blood relative to tumors without MPR. Additionally, the posttreatment tumor bed of patients with MPR was enriched with T-cell clones that had peripherally expanded between weeks 2 and 4 after anti–PD-1 initiation and the intratumoral space occupied by these clonotypes was inversely correlated with percent residual tumor.

Conclusions:

Our study suggests that exchange of T-cell clones between tumor and blood represents a key correlate of pathologic response to neoadjuvant immunotherapy and shows that the periphery may be a previously underappreciated originating compartment for effective antitumor immunity.

See related commentary by Henick, p. 1205
Elimination of Contrast Agent Gadobutrol with Sustained Low Efficiency Daily Dialysis Compared to Intermittent Hemodialysis
Authors: Bunz Hanno , Tschritter Otto , Haap Michael , Riessen Reimer , Heyne Nils , Artunc Ferruh
Published: November 2019

Background: In patients with renal failure, gadolinium-based contrast agents (GBCA) can be removed by intermittent hemodialysis (iHD) to prevent possible toxic effects. There is no data on the efficacy of GBCA removal via sustained low efficiency daily dialysis (SLEDD) which is mainly used in intensive care unit (ICU) patients. Methods: We compared the elimination of the GBCA gadobutrol in 6 ICU patients treated with SLEDD (6–12 h, 90 L dialysate) with 7 normal ward inpatients treated with iHD (4 h, dialysate flow 500 mL/min). Both groups received 3 dialysis sessions on 3 consecutive days starting after the application of gadobutrol. Blood samples were drawn before and after each session and total dialysate, as well as urine was collected. Gadolinium (Gd) concentrations were measured using mass spectrometry and eliminated Gd was calculated from dialysate and urine. Results: The initial mean plasma Gd concentration was 385 ± 183 µM for the iHD and 270 ± 97 µM for the SLEDD group, respectively (p > 0.05). The Gd-reduction rate after the first dialysis session was 83 ± 9 and 67 ± 9% for the iHD and the SLEDD groups, respectively (p = 0.0083). The Gd-reduction rate after the second and third dialysis was 94–98 and 89–96% for the iHD and the SLEDD groups (p > 0.05). The total eliminated Gd was 89 ± 14 and 91 ± 4% of the dose in the iHD and the SLEDD groups, respectively (p > 0.05). Gd dialyzer clearance was 95 ± 22 mL/min and 79 ± 19 mL/min for iHD and SLEDD, respectively (p > 0.05). Conclusions: Gd-elimination with SLEDD is equally effective as iHD and can be safely used to remove GBCA in ICU patients.
Behandlung von Kopf-Hals-Tumoren mittels photodynamischer Therapie mit Redaporfin: ein klinischer Fallbericht
Authors: Oliveira Julio , Monteiro Eurico , Sarmento Cristina , Santos Lúcio Lara , Santos Juliana
Published: November 2019

Fortgeschrittene Plattenepithelkarzinome der Kopf-Hals-Region, die sich nach lokoregionärer Behandlung und mehreren systemischen Therapielinien als refraktär erweisen, stellen eine schwierige therapeutische Herausforderung dar. Der vorliegende Fallbericht schildert ein Erfolgsbeispiel und beschreibt erstmals die Anwendung einer photodynamischen Therapie (PDT) mit Redaporfin gefolgt von einer Immun-Checkpoint-Inhibition mit einem Antikörper gegen PD1. Der betreffende Patient hatte einen umfangreichen Tumor am Mundboden, der nach Chirurgie, Strahlentherapie und zahlreichen Linien systemischer Therapie weiter progredierte. Mit der Redaporfin-PDT wurde sämtliches erkennbares Tumorgewebe zerstört, und die anschließende Anwendung eines Immun-Checkpoint-Inhibitors ermöglichte ein anhaltendes vollständiges Ansprechen. Dieser Fall ist ein Beispiel für die Wirkung dieser Kombinationstherapie und könnte den Weg für eine neue therapeutische Modalität ebnen.
In vitro Evaluation of Solute Removal Characteristics in Intermittent Infusion Hemodiafiltration
Authors: Abe Takayuki , Ishimori Isamu , Murakami Jun , Mineshima Michio , Hanafusa Norio , Nitta Kosaku , Tsuchiya Ken
Published: November 2019

Background: In a typical hemodialysis (HD) session, excessive water removal sometimes induces peripheral circulatory failure and a rapid drop in blood pressure. Intermittent infusion hemodiafiltration (I-HDF), a new modality of dialysis therapy, has been developed to improve peripheral circulation by repeated intermittent infusion of dialysate during an HD session. In a typical I-HDF session, we infuse a volume of 200 mL of ultrapure dialysate by backfiltration at 150 mL/min every 30 min. The same volume is alternately removed from the patient’s blood by filtration at a constant rate after each infusion. However, solute removal characteristics in I-HDF have not been clarified previously. We therefore conducted an in vitro study to investigate the characteristics of solute removal and the factors affecting such removal. Summary: We used human plasma to evaluate the effects of filtration (QF)/infusion (QI) flow rates on solute clearance (CL) and to estimate the time-averaged solute CL (TACL) values. The CL values for all solutes decreased with increasing QI. For small molecules such as urea, the CL values predominantly decreased with increasing QI because of decreasing diffusive transport. For medium and large solutes such as β2 microglobulin or larger, CL values predominantly increased with increasing QF because of increasing convective transport. However, the effects of these changes on TACL values were small compared with the CL value in a typical HD session because of the alternate filtration and infusion in I-HDF. Key Messages: Solute removal characteristics in I-HDF do not differ significantly from those in conventional HD treatment.
Outcomes of Intermittent Infusion Hemodiafiltration in Patients with Cardiac Hypofunction on Maintenance Hemodialysis
Authors: Saito Makoto , Jingu Hiroomi , Oyama Yusuke , Tanaka Toshiyuki , Shiono Akihiko , Machida Masami
Published: November 2019

Background: Following the onset of heart failure symptoms, fluid removal is usually intensified, but patients with decreased cardiac function may develop sudden hypotension due to poor plasma refilling and functional impairment of the mechanisms that maintain blood pressure. In these patients, removal of fluids then becomes difficult. Impairment of the mechanisms that maintain blood pressure can be treated with vasopressors, but intermittent infusion hemodiafiltration (I-HDF) may be effective for managing poor plasma refilling. Thus, here I-HDF was performed in patients with cardiac hypofunction who were undergoing maintenance hemodialysis (HD) in order to assess the clinical effects. Summary: Participants were 5 patients with cardiac hypofunction on maintenance HD. HD and I-HDF were performed for a total of 6 months each. A comparison was made of changes in dry weight (DW) and cardiothoracic ratio (CTR), blood test results, echocardiography findings, plasma ­refilling rate (PRR), and tissue blood flow. During I-HDF, a decrease in DW was achieved and CTR was significantly improved. Echocardiographic findings showed that left ventricular diameter improved significantly during I-HDF. Higher PRR values and increased tissue blood flow were ­observed during I-HDF compared with HD. Intermittent infusions during I-HDF prevented organ ischemia and suppressed the De Jager-Krogh phenomenon. This may be associated with the promotion of stable plasma refilling. Key Messages: Excessive fluid retention is a cause of heart failure symptoms. I-HDF facilitates removal of excessive fluid and thereby possibly contributes to the improvement of cardiac function.
Prevention of Intradialytic Hypotension with Intermittent Back-Filtrate Infusion Haemodiafiltration: Insights into the Underlying Mechanism
Authors: Koda Yutaka , Aoike Ikuo
Published: November 2019

Background: Intradialytic hypotension (IDH) is a major challenge to safely performing haemodialysis. Blood volume depletion due to fluid removal is a major cause of hypotension, so more emphasis should be placed on finding alternative modalities to traditional constant rate ultrafiltration. Summary: Intermittent back-filtrate infusion haemodiafiltration (I-HDF) utilises purified online quality dialysate with an automated dialysis machine. A bolus of 200 mL of dialysate is repetitively infused at 30-min intervals. A pilot study with 68 hypotension-prone patients revealed that I-HDF can reduce the frequency of IDH interventions, particularly in elderly patients and patients with large interdialytic weight gain (IDWG). This was typically accompanied by an increase in intradialytic blood pressure and decreased tachycardia in the latter half of the session, suggesting reduced sympathetic stimulation during I-HDF. Protective mechanisms involved in the pathophysiology of IDH could be explained in part by the findings obtained in this pilot study. Intermittent increases in blood pressure during I-HDF may prevent venous pooling (i.e., the DeJager-Krogh phenomenon), and reduced sympathetic stimulation may maintain a physiological state less likely to induce the cardio-vagal reflex (i.e., the Bezold-Jarisch reflex). The plasma refilling rate (PRR), evaluated as the refilling fraction (RF), is unexpectedly smaller in I-HDF. However, in patients who respond, the RF is well achieved, which suggests that adequate PRR is the central physiology for preventing IDH. Patients for whom I-HDF is effective are characteristically relatively elderly and show increased IDWG. Blood pressure increment and reduced sympathetic activation in I-HDF may be a mechanism for prevention of IDH. Key Messages: Evaluating relative changes in blood volume during I-HDF will provide a new perspective for exploring appropriate ultrafiltration modification that circumvents IDH.
Extended Follow-up of an Educational Intervention Encouraging Appropriate Use of Blood Transfusions
Authors: Pasvolsky Oren , Shepshelovich Daniel , Berger Tamar , Tadmor Boaz , Shochat Tzippy , Raanani Pia , Yahalom Vered , Gafter-Gvili Anat
Published: November 2019

Introduction: A restrictive transfusion strategy of packed red blood cells (PRBCs) has been associated with at least non-inferior patient outcomes in a variety of clinical settings. In December 2014, we conducted an educational intervention which consisted of an oral presentation and computerized notifications at a single tertiary medical center. Objective: The aim of this study was to examine the long-term effects of a simple and low-cost educational intervention aimed to promote awareness to transfusion guidelines. Methods: We retrospectively analyzed all PRBC transfusions ordered between 2014 and 2017. The primary end point was defined as the percentage of PRBC transfused to patients with hemoglobin (Hb) ≥8 g/dL. Results: Between 2014 and 2017, a total of 27,475 PRBCs were transfused in our medical center. There was a continuous reduction in the percentage of PRBCs transfused at a Hb level ≥8 g/dL between 2014 and 2017, with a matching increase in the PRBC percentage trans­fused at Hb <7 g/dL (OR reduction of 42%, 95% CI 0.54–0.62 and OR increase of 68% [95% CI 1.56–1.81], respec­tively). Conclusion: A simple educational intervention likely contributed to sustained improvement in the appropriateness of PRBC transfusions.
The Clinical Significance of Nasal Nitric Oxide Concentrations in Preschool Children with Nasal Inflammatory Disease
Authors: Chen Qiao-bin , Chen Lang , Zheng Xiao-yin , Zheng Xin , Fang Qiong , Xiao Meng , Lin Xiao-ting
Published: November 2019

Background: Allergic rhinitis is an allergic inflammation of the nasal airways, and chronic rhinosinusitis is an inflammation of the paranasal sinuses. It can be induced by infection, allergy, or autoimmune problems. Diagnosis of these two diseases is made primarily based on clinical symptoms, allergen test, and imaging. The allergen test is invasive and expensive. The imaging test is harmful to children. Measurement of nasal nitric oxide (NNO) was noninvasive, without radiation, and inexpensive. This study was to evaluate the clinical significance of NNO in preschool children with nasal inflammatory diseases. Methods: A total of 55 cases of allergic rhinitis, including 35 mild cases and 20 moderate to severe cases, and 33 cases of chronic rhinosinusitis, including 18 mild cases and 15 moderate to severe cases were selected as the experimental group. Fifty healthy preschool children were chosen as the control group. The levels of NNO in all children were measured. The differences in the levels of NNO among allergic rhinitis, chronic rhinosinusitis, and the control group were compared. The levels of NNO in the control group were also analyzed. Results: The levels of NNO were significantly higher in preschool children with allergic rhinitis than in the control group, and the differences were significant. However, the levels of NNO in preschool children with chronic rhinosinusitis were lower than in the control group. In the control group, the levels of NNO were not significantly different between genders, and no significant correlation between NNO levels and the children’s height was found. Conclusion: As a noninvasive method for detecting nasal inflammatory diseases, measuring the levels of NNO had a high clinical significance in preschool children.
Response to BRAF/MEK Inhibition in A598_T599insV BRAF Mutated Melanoma
Authors: Bjursten Sara , Vannas Christoffer , Filges Stefan , Puls Florian , Pandita Ankur , Fagman Henrik , Ståhlberg Anders , Levin Max
Published: November 2019

Approximately 50% of patients with metastatic melanoma harbor an activating BRAF mutation. Tumors with activating mutation BRAF gene proliferate excessively and can be treated with targeted BRAF-inhibitors in combination with MEK inhibitors. The most common BRAF mutation occurs at amino acid position 600. Other BRAF mutations are rare and their predictive value for treatment response to BRAF/MEK inhibition is low. Here, we report on a patient with a BRAF A598_T599insV mutated melanoma, a mutation that has only been described in one previous melanoma patient in which the treatment response to BRAF/MEK inhibition was transient. Our patient had a large ulcerated metastasis that showed a durable complete response implying that BRAF/MEK inhibition should be considered a treatment option for this mutation. We analyzed circulating cell-free tumor DNA (ctDNA) carrying the BRAF A598_T599insV mutation throughout treatment. The allele frequency of BRAF A598_T599insV decreased during regression of the tumors, indicating that this method has potential to monitor treatment response. Our case demonstrates durable response to BRAF/MEK inhibition in a melanoma patient carrying a BRAF A598_T599insV mutation. In addition, we show that allele frequency analysis of A598_T599insV mutation in blood using ultrasensitive sequencing can be used to monitor treatment response.
Choroidal Congestion after Trabeculectomy
Authors: Marenco Maria , Borgia Luigi , Vagge Aldo , Iester Michele
Published: November 2019

The aim of this study is to report a case of choroidal congestion after trabeculectomy. This is a retrospective case report. An 85-year-old male with advanced open-angle glaucoma underwent trabeculectomy in both eyes and during follow-up he complained of visual impairment in the right eye. Thus, spectral domain optical coherence tomography (OCT) was performed and showed choroidal congestion in one eye 1 month after surgery together with a decrease of visual acuity. Symptoms and exam findings resolved with systemic steroids after a 6-month follow-up. OCT is essential for detecting choroidal congestion. This finding can be a possible complication after trabeculectomy and can benefit from steroid treatment.
The Effect of Individualized Developmental Care Practices in Preterm Infants
Authors: Küçük Alemdar Dilek , İnal Sevil
Published: November 2019

Background: Preterm infants are vulnerable humans requiring much care and attention. They may be exposed to irregular noise, light, and odor in the neonatal intensive care unit for a period of several weeks or months. This study was carried out to determine the effect of individualized developmental care on physiological parameters, growth, and transition to oral feeding in preterm infants. Methods: The study was a randomized controlled trial. The sample comprised premature infants meeting the inclusion criteria. They were randomly assigned to four groups: the maternal voice group, the breast milk odor (BMO) group, the incubator cover (IC) group, and the control group. Results: No statistically significant difference was found between the groups in terms of weight, height, and head circumference at time of discharge. Mean SO2 values were statistically higher in the IC group than the other groups; however, the heart rate and respiratory rate were not statistically different in a significant sense between the groups. The briefest duration of transition to total oral feeding was seen in the BMO group. Conclusion: Individualized developmental care practices based on the results of these interventions are likely to support the care of preterm infants. Breast milk odor may ease the transition to breastfeeding.
Combination of Local Ablative Therapy and Continuation of Immune Checkpoint Inhibitor (ICI) Therapy Provides Durable Treatment Response Past Oligometastatic Progression in NSCLC: A Case Report
Authors: Griswold Cassia R. , Kerrigan Katie , Patel Shiven B.
Published: November 2019

Adenosquamous carcinoma is a rare type of non-small cell lung cancer associated with advanced disease and poor prognosis. There is limited data for the management of mixed histology disease in elderly or frail patients. A 79-year-old woman with no smoking history presented with a right upper lobe lung mass on chest x-ray. Biopsy of the mass demonstrated an EGFR-amplified, PD-L1 positive adenosquamous lung cancer. The mass was surgically resected but the patient was not a candidate for adjuvant chemotherapy. The patient later developed a metastatic paraspinal lesion that was successfully managed with SBRT. Approximately six months later, the patient developed adrenal metastases and pembrolizumab was initiated. After three cycles of systemic therapy, she developed subcutaneous lesions in her back and chest wall, which were managed with palliative resection. Scans demonstrate stable disease and continued responsiveness to pembrolizumab over one year from the most recent local ablative therapy. This case illustrates the potential role of local ablative therapy for oligometastatic progression, as it may confer significant benefit in elderly patients or those with a more indolent disease course. Additionally, we have demonstrated that continuing immunotherapy past progression is reasonable in patients with no viable alternate therapy options, as delayed responses may occur.