bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma IL8 Is a Biomarker for TAK1 Activation and Predicts Resistance to Nanoliposomal Irinotecan in Patients with Gemcitabine-Refractory Pancreatic Cancer
Authors: Merz Valeria , Zecchetto Camilla , Santoro Raffaela , Simionato Francesca , Sabbadini Fabio , Mangiameli Domenico , Piro Geny , Cavaliere Alessandro , Deiana Michela , Valenti Maria Teresa , Bazan Diana , Fedele Vita , Lonardi Sara , Melisi Davide 
Published: June 2020

AbstractPurpose:Pancreatic cancer is one of the most lethal solid tumors, mainly because of its intrinsic chemoresistance. We identified TAK1 as a central hub sustaining this resistance. Nanoliposomal irinotecan (nal-IRI) is a novel treatment for metastatic gemcitabine-refractory pancreatic cancer. We endeavored to identify circulating markers for TAK1 activation predicting chemoresistance in this setting.Experimental Design:In vivo activity of nal-IRI was validated in an orthotopic nude murine model expressing TAK1-specific shRNA. Plasma concentration of 20 different cytokines were measured by a multiplex xMAP/Luminex technology in patients prospectively enrolled to receive nal-IRI plus 5-fluorouracil/leucovorin (5-FU/LV). The optimal cutoff thresholds able to significantly predict patients' outcome were obtained on the basis of the maximization of the Youden's statistics.Results:Differential expression profiling revealed the gene coding for IL8 as the most significantly downregulated in shTAK1 pancreatic cancer cell lines. Mice bearing shTAK1 tumors had significantly lower plasma levels of IL8 and experienced a significant reduction in tumor growth if treated with nal-IRI, whereas those bearing TAK1-proficient tumors were resistant to this agent. In a discovery cohort of 77 patients, IL8 was the circulating factor most significantly correlated with survival (plasma levels lower vs higher than cutoff: mPFS 3.4 months vs 2.8 months; hazard ratio [HR], 2.55; 95% CI, 1.39–4.67; P = 0.0017; median overall survival 8.9 months vs 5.3 months; HR, 3.51; 95% CI, 0.84–6.68; P = 4.9e−05). These results were confirmed in a validation cohort of 50 patients.Conclusions:Our study identified IL8 as the most significant circulating factor for TAK1 pathway activation and candidates IL8 as a potential predictive biomarker of resistance to nal-IRI in gemcitabine-refractory patients with pancreatic cancer.
Immunotherapy of Ipilimumab and Nivolumab in Patients with Advanced Neuroendocrine Tumors: A Subgroup Analysis of the CA209-538 Clinical Trial for Rare Cancers
Authors: Klein Oliver , Kee Damien , Markman Ben , Michael Michael , Underhill Craig , Carlino Matteo S. , Jackett Louise , Lum Caroline , Scott Clare , Nagrial Adnan , Behren Andreas , So Jane Y. , Palmer Jodie , Cebon Jonathan 
Published: June 2020

Abstract

Purpose:
Combination immunotherapy with anti–CTLA-4 and anti–PD-1 blockade has demonstrated significant clinical activity across several tumor types. Neuroendocrine tumors (NET) are a heterogeneous group of rare tumors with limited treatment options. CA209-538 is a clinical trial of combination immunotherapy with ipilimumab and nivolumab in rare cancers, including advanced NETs.

Patients and Methods:
CA209-538 is a prospective multicenter clinical trial in patients with advanced rare cancers. Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every three weeks for four doses, followed by nivolumab 3 mg/kg every two weeks and continued for up to 96 weeks, until disease progression or the development of unacceptable toxicity. Response was assessed every 12 weeks by RECIST 1.1. The primary endpoint was clinical benefit rate (CBR; complete remission + partial remission + stable disease).

Results:
Twenty-nine patients with advanced NETs received treatment. Three (10%) patients had low-, 13 (45%) had intermediate-, and 13 (45%) had high-grade tumors; lung was the most common primary site (39%). The objective response rate was 24% with a CBR of 72%; 43% of patients with pancreatic neuroendocrine neoplasms (NEN), and 33% of patients with atypical bronchial carcinoid achieved an objective response. The median progression-free survival was 4.8 months [95% confidence interval (CI): 2.7–10.5] and overall survival was 14.8 months (95% CI: 4.1–21.3). Immune-related toxicity was reported in 66% of patients with 34% experiencing grade 3/4 events.

Conclusions:
Combination immunotherapy with ipilimumab and nivolumab demonstrated significant clinical activity in subgroups of patients with advanced NETs including patients with atypical bronchial carcinoid and high-grade pancreatic NENs.
TargetingMETDysregulation in Cancer
Authors: Recondo Gonzalo , Che Jianwei , Jänne Pasi A. , Awad Mark M. 
Published: June 2020

AbstractAberrant MET signaling can drive tumorigenesis in several cancer types through a variety of molecular mechanisms including MET gene amplification, mutation, rearrangement, and overexpression. Improvements in biomarker discovery and testing have more recently enabled the selection of patients with MET-dependent cancers for treatment with potent, specific, and novel MET-targeting therapies. We review the known oncologic processes that activate MET, discuss therapeutic strategies for MET-dependent malignancies, and highlight emerging challenges in acquired drug resistance in these cancers.Significance:Increasing evidence supports the use of MET-targeting therapies in biomarker-selected cancers that harbor molecular alterations in MET. Diverse mechanisms of resistance to MET inhibitors will require the development of novel strategies to delay and overcome drug resistance.
Genetic Basis and Prognostic Value of Exercise QT Dynamics
Authors: van Duijvenboden Stefan , Ramírez Julia , Young William J. , Mifsud Borbala , Orini Michele , Tinker Andrew , Munroe Patricia B. , Lambiase Pier D. 
Published: June 2020

Background:
Abnormal QT interval responses to heart rate (QT dynamics) is an independent risk predictor for cardiovascular disease in patients, but its genetic basis and prognostic value in a population-based cohort have not been investigated.

Methods:
QT dynamics during exercise and recovery were derived in 56 643 individuals from UK Biobank without a history of cardiovascular events. Genome-wide association studies were conducted to identify genetic variants and bioinformatics analyses were performed to prioritize candidate genes. The prognostic value of QT dynamics was evaluated for cardiovascular events (death or hospitalization) and all-cause mortality.

Results:

Heritability of QT dynamics during exercise and recovery were 10.7% and 5.4%, respectively. Genome-wide association studies identified 20 loci, of which 4 loci included genes implicated in mendelian long-QT syndrome. Five loci did not overlap with previously reported resting QT interval loci; candidate genes included
KCNQ4
and
KIAA1755
. Genetic risk scores were not associated with cardiovascular events in 357 882 unrelated individuals from UK Biobank. We also did not observe associations of QT dynamics during exercise and recovery with cardiovascular events. Increased QT dynamics during recovery was significantly associated with all-cause mortality in the univariate Cox regression analysis (hazard ratio, 1.09 [95% CI, 1.05–1.13],
P
=2.28×10
-5
), but the association was not significant after adjusting for clinical risk factors.

Conclusions:
QT interval dynamics during exercise and recovery are heritable markers but do not carry independent prognostic information for clinical outcomes in the UK Biobank, a population-based cohort. Their prognostic importance may relate to cardiovascular disease cohorts where structural heart disease or ischemia may influence repolarization dynamics. The strong overlap between QT dynamics and resting QT interval loci suggests common biological pathways; however, nonoverlapping loci suggests alternative mechanisms may exist that underlie QT interval dynamics.
Autonomic Activity during a Daytime Nap Facilitates Working Memory Improvement
Authors: Chen Pin-Chun , Whitehurst Lauren N. , Naji Mohsen , Mednick Sara C. 
Published: June 2020

Abstract
Recent investigations have implicated the parasympathetic branch of the autonomic nervous system in higher-order executive functions. These actions are purported to occur through autonomic nervous system's modulation of the pFC, with parasympathetic activity during wake associated with working memory (WM) ability. Compared with wake, sleep is a period with substantially greater parasympathetic tone. Recent work has reported that sleep may also contribute to improvement in WM. Here, we examined the role of cardiac parasympathetic activity during sleep on WM improvement in healthy young adults. Participants were tested in an operation span task in the morning and evening, and during the intertest period, participants experienced either a nap or wake. We measured high-frequency heart rate variability as an index of cardiac, parasympathetic activity during both wake and sleep. Participants showed the expected boost in parasympathetic activity during nap, compared with wake. Furthermore, parasympathetic activity during sleep, but not wake, was significantly correlated with WM improvement. Together, these results indicate that the natural boost in parasympathetic activity during sleep may benefit gains in prefrontal executive function in young adults. We present a conceptual model illustrating the interaction between sleep, autonomic activity, and prefrontal brain function and highlight open research questions that will facilitate understanding of the factors that contribute to executive abilities in young adults as well as in cognitive aging.
Sequence Memory in the Hippocampal–Entorhinal Region
Authors: Bellmund Jacob L. S. , Polti Ignacio , Doeller Christian F. 
Published: June 2020

Abstract
Episodic memories are constructed from sequences of events. When recalling such a memory, we not only recall individual events, but we also retrieve information about how the sequence of events unfolded. Here, we focus on the role of the hippocampal–entorhinal region in processing and remembering sequences of events, which are thought to be stored in relational networks. We summarize evidence that temporal relations are a central organizational principle for memories in the hippocampus. Importantly, we incorporate novel insights from recent studies about the role of the adjacent entorhinal cortex in sequence memory. In rodents, the lateral entorhinal subregion carries temporal information during ongoing behavior. The human homologue is recruited during memory recall where its representations reflect the temporal relationships between events encountered in a sequence. We further introduce the idea that the hippocampal–entorhinal region might enable temporal scaling of sequence representations. Flexible changes of sequence progression speed could underlie the traversal of episodic memories and mental simulations at different paces. In conclusion, we describe how the entorhinal cortex and hippocampus contribute to remembering event sequences—a core component of episodic memory.
Love and Death: Theoretical and Practical Examination of Human-Animal Relations in Creating Wild Animal Osteobiography
Authors: Hull Emily H. 
Published: June 2020

Abstract
Osteobiographies are a common form of presenting the archaeological analysis of the life history of an individual. This form of analysis, however, is usually reserved for human subjects. Writing an osteobiography of a nonhuman person is complicated by the lack of human understanding of animal thought and experience. Such analysis is further complicated when the subject is not a companion animal, and isolated from human funerary rituals which may shed light on the animal’s life. The skeletal remains of an injured wild caribou from Alberta who was collected as a museum specimen presents a unique opportunity to understand an individual animal’s life, as well presents an example of the complexities of human-animal relationships in an analytical setting. This study examines both the life of an extraordinary nonhuman person and the impact of reconstructing nonhuman life histories on the analyst.
Long noncoding RNA SNHG12 promotes the proliferation, migration, and invasion of trophoblast cells by regulating the epithelial–mesenchymal transition and cell cycle
Authors: Zhou Fenmei , Sun Yanlan , Chi Zhenjing , Gao Qiong , Wang Hairong 
Published: June 2020

Objective The deficient placental blood perfusion caused by the attenuated infiltration of trophoblast cells is a key factor in the occurrence of preeclampsia (PE). Furthermore, the long noncoding (lnc)RNA SNHG12 (small nucleolar RNA host gene 12) can promote the proliferation and metastasis of multiple tumor cells. However, whether lncRNA SNHG12 affects proliferation and metastasis of trophoblast cells is unclear. Methods We examined the level of lncRNA SNHG12 in plasma and placenta of patients with PE and constructed trophoblast cells with overexpressed or knocked down SNHG12. CCK-8, wound healing, and Transwell assays were used to detect alterations in proliferation, migration, and invasion of trophoblast cells. Western blotting was used to detect proteins related to the epithelial–mesenchymal transition (EMT), and cell cycle assays clarified cell cycle distribution. Results LncRNA SNHG12 promoted the proliferation, migration, and invasion of trophoblast cells. The expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, β-catenin, and vimentin were positively correlated with SNHG12, and expression of E-cadherin was negatively correlated with SNHG12. SNHG12 also promoted the transition of trophoblast cells from G0/G1 to S phase. Conclusion Overall, lncRNA SNHG12 promoted the migration and invasion of trophoblast cells by inducing the progression of EMT.
Pooled analysis of the efficacy and safety of adjunctive alpha-blocker therapy before ureteroscopy in the management of ureteral stones
Authors: Tan Hailin , Li Yanjiang , Zhang Xiaofei , Mao Xin 
Published: June 2020

Objective To evaluate the efficacy and safety of adjunctive alpha-blocker therapy before ureteroscopy in the management of ureteral stones. Methods The databases MEDLINE®, EMBASE and The Cochrane Controlled Trail Register of Controlled Trials were searched between January 1980 and June 2019 to identify randomized controlled trials (RCTs) that referred to the use of alpha-blockers as adjunctive therapy before ureteroscopy for the treatment of ureteral stones. Odds ratios (ORs) with 95% confidence intervals (CIs) were used for dichotomous outcomes; and mean difference (MD) with 95% CIs were used to report continuous outcomes. Results The analysis included five RCTs with a total of 557 patients. Compared with placebo, patients that received adjunctive alpha-blockers had significantly higher successful access to the stone (OR 5.44; 95% CI 2.99, 9.88), a significantly higher stone-free rate at the end of week 4 (OR 3.75; 95% CI 2.20, 6.39), significantly less requirement for balloon dilatation (OR 0.26; 95% CI 0.15, 0.44) and a significantly lower risk of complications (OR 0.25; 95% CI 0.15, 0.42). There was no significant difference in the operation time between the two groups (MD –3.33; 95% CI –7.03, 0.37). Conclusions Adjunctive alpha-blocker therapy administered before ureteroscopy was effective in the management of ureteral stones with a lower risk of complications than placebo treatment.
Babao Dan inhibits the migration and invasion of gastric cancer cells by suppressing epithelial–mesenchymal transition through the TGF-β/Smad pathway
Authors: Liu Jianxin , Chen Yongan , Cao Zhiyun , Guan Bin , Peng Jun , Chen Youqin , Zhan Zhixue , Sferra Thomas Joseph , Sankararaman Senthilkumar , Lin Jiumao 
Published: June 2020

Objective To investigate the anti-metastatic effects of Babao Dan (BBD) on gastric cancer (GC) cells (AGS and MGC80-3) and explore the underlying molecular mechanisms by which it inhibits epithelial–mesenchymal transition (EMT). Methods AGS and MGC80-3 cells were treated with BBD. In addition, cells were treated with the EMT inducer transforming growth factor-β1 (TGF-β1). Cell viability was determined using the MTT assay, and the live cell ratio was calculated via cell counting. Cell invasion and migration were evaluated using the Transwell assay. Western blotting was performed to measure the protein expression of EMT biomarkers and related genes. Results BBD inhibited the viability, migration, and invasion of AGS and MGC80-3 cells, but it did not reduce the live cell ratio. Furthermore, BBD inhibited the expression of N-cadherin, vimentin, zinc finger E-box binding homeobox (ZEB)1, ZEB2, Twist1, matrix metalloproteinase (MMP)2, MMP9, TGF-β1, and p-Smad2/3, whereas E-cadherin expression was increased in AGS and MGC80-3 cells to different degrees. Using a GC cell model of EMT induced by TGF-β1, we proved that BBD inhibited p-Smad2/3 and N-cadherin expression, cell migration, and cell invasion. Conclusion BBD suppressed cell migration and invasion by inhibiting TGF-β–induced EMT and inactivating TGF-β/Smad signaling in GC cells.
Combining interferon-γ release assays with lymphocyte enumeration for diagnosis of Mycobacterium tuberculosis infection
Authors: Lv Dingfeng , Liu Yanqing , Guo Fei , Wu Aihua , Mo Yijun , Wang Shanshan , Chu Jinguo 
Published: June 2020

Objective To investigate the possibility of combining tuberculosis (TB)-interferon (IFN)-γ release assays (IGRAs) with lymphocyte enumeration for diagnosis of Mycobacterium tuberculosis infection. Methods We performed a retrospective study of 166 TB patients [68 patients with pulmonary tuberculosis TB (PTB) and 98 patients with extra-pulmonary TB (EPTB)] diagnosed in our hospital between January 2016 and May 2018 along with 377 non-TB patients. The diagnostic performance of the TB-IGRA was evaluated using receiver operating characteristic (ROC) curves. Youden’s index was used to determine the optimal cut-off threshold. Results IFN-γ release in patients with PTB and EPTB were dramatically higher compared with non-TB patients (203.58±18.00 pg/mL, 201.83±14.56 pg/mL and 32.12±4.36 pg/mL, respectively). IFN-γ release was positively correlated with lymphocyte counts and percentages in patients with PTB (r = 0.252 and r = 0.278, respectively) and EPTB (r = 0.229 and r = 0.298, respectively). No correlation was observed in non-TB patients. The area under the ROC curve for TB-IGRA was 0.884. When the optimal cut-off value for IFN-γ (14 pg/mL, Youden’s index 0.661) was applied, the sensitivity was 88.6% and the specificity was 77.5%. Conclusions Combining TB-IGRA with lymphocyte enumeration was effective for diagnosis of early-stage Mycobacterium tuberculosis infection.
The anti-alcohol dependency drug disulfiram inhibits the viability and progression of gastric cancer cells by regulating the Wnt and NF-κB pathways
Authors: Zhang Jun , Pu Ke , Bai Suyang , Peng Yukui , Li Fan , Ji Rui , Guo Qinghong , Sun Weiming , Wang Yuping 
Published: June 2020

Objective Disulfiram is commonly used for alcohol abuse; however, recent studies have revealed its potential as an anti-cancer treatment. This study investigated the effects of disulfiram on gastric cancer and its underlying mechanisms of action. Methods The gastric cancer cell lines MKN-45 and SGC-7901 were used for all experiments. Cell proliferation was investigated using cell counting kit-8, cell migration and invasion were examined using Transwell assays, the proliferation and metastasis related proteins PCNA and MMP-2, respectively, were detected by ELISA. To explore the underlying molecular mechanisms, we also examined levels of proteins involved in the Wnt and NF-κB pathways by ELISA. Results Disulfiram significantly inhibited the proliferation, migration, and invasion of gastric cancer cells and decreased PCNA and MMP-2 levels. Additionally, disulfiram-treated MKN-45 and SGC-7901 cells showed reduced expression of Wnt, β-catenin, and NF-κB. Conclusion Disulfiram regulates the Wnt and NF-κB pathways, and thus could be a potential treatment for managing gastric cancer.
Influence of temperature and humidity on hand, foot, and mouth disease in Guangzhou, 2013–2017
Authors: Chen Chun , Jiang Qinqin , Song Zhuangzhi , Li Yilan , Wang Hui , Lu Ying , Wang Dahu , Li Meixia , Li Tiegang 
Published: June 2020

Objective To explore associations between temperature, humidity and hand, foot and mouth disease (HFMD) incidence in Guangzhou, China from 2013 to 2017. Methods A distributed lag non-linear model was applied to estimate the effects of daily temperature and humidity on HFMD incidence after adjusting for long-term trends, seasonal trends, and day of the week. Results In total, 353,431 confirmed HFMD cases were reported in Guangzhou over the study period. A bimodal seasonal pattern was observed. High temperatures had acute short-term effects on HFMD incidence that declined quickly over time. The effects of low humidity declined over lag periods, but increased when the humidity surpassed 60.5%. Temperature and humidity were both inversely associated with HFMD incidence during lag days 0 to 3 and with lag periods Conclusions Temperature and humidity play important roles in HFMD incidence. These data are important for developing public health strategies.
‘You actually see what occupational therapists do in real life’: Outcomes and critical features of first-year practice education placements
Authors: Honey Anne , Penman Merrolee 
Published: June 2020

Introduction First-year practice education placements have numerous benefits for occupational therapy students but are resource intensive. In considering alternatives, it is critical to consider students’ voices to ensure that planned experiences enable students to achieve the outcomes they value and need. This study examined undergraduate occupational therapy students’ views about important outcomes and characteristics of first-year placements. Methods Focus groups were conducted with 18 occupational therapy students and analysed using constant comparative analysis. Findings Two overarching outcomes were valued: confirmation of occupational therapy as a career choice and experience to draw on for future learning and practice. These outcomes were achievable through four proximal outcomes: understanding occupational therapy; understanding clients; finding out about myself and developing skills. The extent to which the valued outcomes were attained was determined by eight critical experiences: observing an occupational therapist in action; seeing real clients with real issues; seeing positive impact; seeing the bigger picture; accessing the occupational therapist’s reasoning; hands-on doing; getting feedback on skills and thinking analytically/reflectively. Conclusion In designing first-year placements, practice educators and academics need to ensure that students are provided with experiences that incorporate reality, participation and making connections to a bigger picture of occupational therapy service provision.
TransPRK treatment for residual refractive error and induced aberrations in eye undergone SMILE treatment
Authors: de Ortueta Diego , von Rüden Dennis , Verma Shwetabh , Arba-Mosquera Samuel 
Published: June 2020

In this case report, we propose to correct refractive errors after SMILE a refractive lenticule surgery technique with transepithelial Photorefractive keratectomy (TransPRK). The advantage of this technique is that the measured aberrations with topography o the Cornea are also treated on the Surface of the Cornea.