bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dignity of the patient-–family unit: further understanding in hospice palliative care
Authors: Guo Qiaohong , Zheng Ruishuang , Jacelon Cynthia S , McClement Susan , Thompson Genevieve , Chochinov Harvey 
Published: July 2019

ObjectivesThis study aimed to explore the construct of dignity of the patient–family dyad in hospice palliative care, as well as its influencing factors from the perspective of hospice palliative care staff.MethodsA qualitative descriptive study was conducted with 34 staff members from a residential hospice in Amherst, USA, and an inpatient palliative care unit in Winnipeg, Canada, between September 2013 and December 2016. Data were collected through semistructured interviews and were analysed using the thematic analysis approach.ResultsFindings suggested that staff members viewed dignity as something that is reciprocally supported within the patient–family unit. Themes including respect, comfort, privacy, being informed and quality family time were common in the conceptualisation of dignity in patients and families; themes of being human and being self, autonomy and living with dignity were uniquely used to conceptualise patient dignity. Themes solely constituting family dignity included being included in care, being capable and being treated fairly. Cultural considerations, environmental factors, teamwork and patient/family–staff relationship were the factors identified by staff members that affected dignity in hospice palliative care.ConclusionFindings of this study provide insights into the development of strategies to support the dignity of the patient–family unit in hospice palliative care.
Association of lipoprotein subfractions and glycoprotein acetylation with coronary plaque burden in SLE
Authors: Purmalek Monica M , Carlucci Philip M , Dey Amit K , Sampson Maureen , Temesgen-Oyelakin Yenealem , Sakhardande Simantini , Lerman Joseph B , Fike Alice , Davis Michael , Chung Jonathan H , Salahuddin Taufiq , Manna Zerai , Gupta Sarthak , Chen Marcus Y , Hasni Sarfaraz , Mehta Nehal N , Remaley Alan , Kaplan Mariana J 
Published: July 2019

ObjectiveSubjects with SLE display an enhanced risk of atherosclerotic cardiovascular disease (CVD) that is not explained by Framingham risk. This study sought to investigate the utility of nuclear MR (NMR) spectroscopy measurements of serum lipoprotein particle counts and size and glycoprotein acetylation (GlycA) burden to predict coronary atherosclerosis in SLE.MethodsCoronary plaque burden was assessed in SLE subjects and healthy controls using coronary CT angiography. Lipoproteins and GlycA were quantified by NMR spectroscopy.ResultsSLE subjects displayed statistically significant decreases in high-density lipoprotein (HDL) particle counts and increased very low-density lipoprotein (VLDL) particle counts compared with controls. Non-calcified coronary plaque burden (NCB) negatively associated with HDL subsets whereas it positively associated with VLDL particle counts in multivariate adjusted models. GlycA was significantly increased in SLE sera compared with controls. In contrast to high-sensitivity C reactive protein, elevations in GlycA in SLE significantly associated with NCB and insulin resistance (IR), though the association with NCB was no longer significant after adjusting for prednisone use.ConclusionsPatients with SLE display a proatherogenic lipoprotein profile that may significantly contribute to the development of premature CVD. The results demonstrate that NMR measures of GlycA and lipoprotein profiles, beyond what is captured in routine clinical labs, could be a useful tool in assessing CVD risk in patients with SLE.
Sex-dependent prolongation of sciatic nerve blockade in diabetes patients: a prospective cohort study
Authors: Tang Shuai , Wang Jin , Tian Yi , Li Xu , Cui Qiuju , Xu Mei , Song Xiaojun , Zheng Yuehong , Yang Hongbo , Ma Chao , Zhan Lujing , Zhu Chaonan , Zhang Yuelun , Yao Min , Huang Yuguang 
Published: July 2019

IntroductionDiabetes may affect the duration of nerve block after regional anesthesia. This study aimed to compare the durations of sensory and motor block in diabetes versus non-diabetes patients after lower limb nerve block and delineate any sex-based differences in the duration of sensory and motor blocks of both diabetes and non-diabetes patients.MethodsThis prospective single-blinded cohort study recruited 86 patients who underwent unilateral lower extremity surgery; 52 patients were non-diabetic and 34 were diabetic. Each patient received an ultrasound-guided nerve stimulator-assisted subgluteal sciatic nerve block with 0.75% ropivacaine. Duration of sensory block was assessed with the Semmes-Weinstein monofilament test, and duration of motor block was assessed with dorsal and plantar flexion of the foot.ResultsThe sensory and motor block durations of diabetes patients were significantly prolonged versus non-diabetes patients (19.8±6.0 hours vs 15.6±5.1 hours; p<0.05) and (19.5±8.1 hours vs 14.8±5.7 hours, p=0.005), respectively. The durations of sensory and motor block were comparable between male diabetes and non-diabetes patients, but they were significantly longer in female diabetes patients. Multiple regression analysis further revealed that, after adjustment for age and preoperative sensory threshold, diabetes, fasting plasma glucose and HbA1c levels were signiﬁcantly associated with sensory and motor blocks. Sex analysis showed the association was only present in female diabetes patients, not male diabetes patients.ConclusionThe durations of sensory and motor block are significantly prolonged after subgluteal sciatic nerve block in diabetes patients. Furthermore, the prolonged nerve blockade is present only in diabetes women, not diabetes men.Trial registration numberNCT02482831.
Modal analysis and experimental research on a planetary reducer with small tooth number difference
Authors: Huang Chao , Huang Baiyue , Zhang Yi , Xiao Ke 
Published: July 2019

To comprehensively analyze the modal characteristics of the planetary reducer with small tooth number difference, based on shaft–bearing–gear–shell coupling, a finite element modal analysis model was established in ABAQUS. The teeth meshing sites were constrained by binding, bearings were simulated by spring elements, and then the natural frequencies and corresponding vibration modes of the reducer were obtained by applying the Lanczos method. Further, a hammering modal experiment on the reducer was carried out utilizing LMS Test.Lab. The modal data were analyzed using a modal identification method, and the modal frequencies and damping ratios were achieved, also the experimental modal parameters were validated according to the modal assurance criterion. The research results indicate that the lowest-order natural frequency of the reducer is 148.53 Hz, which is much higher than the rotation frequency of the eccentric shaft, double gear, and output gear. Also, the two-stage gear mesh frequencies are away from the natural frequencies, therefore the reducer under normal operating conditions will not cause coupling resonance. This research provides a theoretical basis and experimental reference for the dynamic structure optimization of the planetary reducer.
Notes from the Pier No. 1(3)
Authors: Huang Chihlien 
Published: July 2019

Based on the two previous notes, this paper argues that if China’s national as well as international development programs are actually a configuration of inter-connectivity, then the Shanghai Communique (February, 1972) can be taken as a midway station between the Russia Aid Programs (1950s), the Bandung Declaration (1956) and the Pan American Highway and BRI-OBOR could be taken as a continental inter-connectivity. From there on, an Arctic OBOR would result in a super inter-hemispheric OBOR, thus bringing human civilizations to move from “#1.0” to “#2.0” and on to their “#3.0 Paradigm shift”.In addition to big nations such as China, EU, Russia, and the US playing their leading roles, many other nations along the road would be able to participate in the process and share its rewards.
APE1 Upregulates MMP-14 via Redox-Sensitive ARF6-Mediated Recycling to Promote Cell Invasion of Esophageal Adenocarcinoma
Authors: Lu Heng , Bhat Ajaz A. , Peng Dunfa , Chen Zheng , Zhu Shoumin , Hong Jun , Maacha Selma , Yan Jin , Robbins David J. , Washington M. Kay , Belkhiri Abbes , El-Rifai Wael 
Published: July 2019

Abstract

Esophageal adenocarcinoma (EAC) is an aggressive malignancy with poor clinical outcome. The incidence of EAC has been rising rapidly in the past three decades. Here, we showed that apurinic/apyrimidinic endonuclease (APE1) is overexpressed in EAC cell lines, and patients' samples of dysplasia and EAC. Downregulation of APE1 or inhibition of its redox function significantly repressed invasion. Overexpression of a redox-defective mutant, C65A, abrogated the proinvasive phenotype of APE1. APE1 regulated invasion via upregulation of matrix metalloproteinase 14 (MMP-14), which subsequently activated MMP-2, leading to degradation of the extracellular matrix in a redox-dependent manner. Downregulation of APE1 or inhibition of its redox function decreased the rate of endocytosis and recycling of MMP-14 protein. APE1 interacted with ARF6, a key regulator of MMP-14 recycling, which maintained ARF6 activity in an APE1-redox–dependent manner, promoting its ability to regulate MMP-14 recycling to the cell surface. In summary, these findings identify a novel redox-sensitive APE1–ARF6–MMP-14 signaling axis that mediates cellular invasion in esophageal carcinogenesis.

Significance:
This study demonstrates the association between oxidative stress and the development and metastatic behavior of esophageal adenocarcinoma.
The Gut Microbiome: A New Player in Breast Cancer Metastasis
Authors: Ingman Wendy V. 
Published: July 2019

Abstract
There is increasing interest in the role of the gut microbiome in health and disease, and a number of observational and in vitro studies have suggested it may play a role in breast cancer development and progression. Buchta Rosean and colleagues present the first functional evidence that a preexisting disturbance in the gut microbiome leads to increased breast cancer cell metastasis in a mouse model. This discovery places the gut microbiome as a new player in breast cancer metastasis; however, further studies are required to determine the relevance of the findings in this mouse model to human disease. A better understanding of the relationship between the bacterial ecosystem of the gut and progression of breast cancer has enormous potential for improving treatment outcomes for patients with breast cancer.
See related article by Buchta Rosean et al., p. 3662
Molecular and Clinical Activity of CDX-3379, an Anti-ErbB3 Monoclonal Antibody, in Head and Neck Squamous Cell Carcinoma Patients
Authors: Duvvuri Umamaheswar , George Jonathan , Kim Seungwon , Alvarado Diego , Neumeister Veronique M. , Chenna Ahmed , Gedrich Richard , Hawthorne Thomas , LaVallee Theresa , Grandis Jennifer R. , Bauman Julie E. 
Published: July 2019

AbstractPurpose:ErbB3 and its ligand neuregulin-1 (NRG1) are widely expressed in head and neck squamous cell carcinoma (HNSCC) and associated with tumor progression. A “window-of-opportunity” study (NCT02473731) was conducted to evaluate the pharmacodynamic effects of CDX-3379, an anti-ErbB3 mAb, in patients with HNSCC.Patients and Methods:Twelve patients with newly diagnosed, operable HNSCC received two infusions of CDX-3379 (1,000 mg) at a 2-week interval prior to tumor resection. The primary study objective was to achieve ≥50% reduction in tumor ErbB3 signaling (phosphorylation of ErbB3; pErbB3) in ≥30% of patients. Other potential tumor biomarkers, pharmacokinetics, safety, and tumor measurements were also assessed.Results:pErbB3 was detectable in all tumors prior to treatment and decreased for 10 of 12 (83%) patients following CDX-3379 dosing, with ≥50% reduction in 7 of 12 (58%; P = 0.04; 95% confidence interval, 27.7%–84.8%). Target trough CDX-3379 serum levels were achieved in all patients. CDX-3379 treatment–related toxicity was grade 1–2 and included diarrhea, fatigue, and acneiform dermatitis. Five of 12 (42%) patients had shrinkage in tumor burden, including a marked clinical response in a patient with human papillomavirus–negative oral cavity HNSCC. All patients with tumor shrinkage had tumors that expressed both NRG1 and ErbB3 and demonstrated reduced pErbB3 with CDX-3379 treatment.Conclusions:This study demonstrates that CDX-3379 can inhibit tumor ErbB3 phosphorylation in HNSCC. CDX-3379 was well tolerated and associated with measurable tumor regression. A phase II study (NCT03254927) has been initiated to evaluate CDX-3379 in combination with cetuximab for patients with advanced HNSCC.
Dose-Ranging and Cohort-Expansion Study of Monalizumab (IPH2201) in Patients with Advanced Gynecologic Malignancies: A Trial of the Canadian Cancer Trials Group (CCTG): IND221
Authors: Tinker Anna V. , Hirte Holger W. , Provencher Diane , Butler Marcus , Ritter Heather , Tu Dongsheng , Azim Hatem A. , Paralejas Paulo , Grenier Nathalie , Hahn Shirley-Ann , Ramsahai Janelle , Seymour Lesley 
Published: July 2019

AbstractPurpose:Monalizumab binds CD94/NKG2A, preventing HLA-E inhibition of tumor lymphocytes. A dose-ranging/cohort expansion trial of monalizumab for recurrent gynecologic malignancies was conducted to determine the recommended phase II dose (RP2D) and to explore clinical activity, pharmacokinetics, pharmacodynamics, safety, and immunogenicity.Patients and Methods:Participants (and part 2 expansion cohorts) included (i) platinum-sensitive ovarian, (ii) platinum-resistant ovarian, (iii) squamous cervical (CX), and (iv) epithelial endometrial (END) carcinomas. Part 1 assessed monalizumab at 1, 4, or 10 mg/kg every 2 weeks. In part 2, ≥4 patients/cohort underwent pre- and on-treatment tumor biopsies. Preset criteria determined cohort expansion.Results:A total of 58 participants were evaluable. The RP2D was 10 mg/kg i.v. every 2 weeks. Dose proportionality and 100% NKG2A saturation were observed. Related adverse events were mild: headache, abdominal pain, fatigue, nausea, and vomiting. Grade 3 related adverse events were nausea (1), vomiting (1), dehydration (1), fatigue (2), anorexia (1), dyspnea (1), and proctitis (1). Dose-limiting toxicities were not observed. Hematologic and biochemical changes were mild and not dose related. Best response was SD: part 1, 7 of 18 (39%) [3.4 months (1.4–5.5)], and part 2, 7 of 39 (18%) [1.7 months (CX) to 14.8 months (END)]. Neither a predictive biomarker for SD nor evidence of pharmacodynamic effects was identified. There was a trend to significance between a reduction in lymphocyte HLA-E total score and pharmacodynamics.Conclusions:Monalizumab 10 mg/kg i.v. every 2 week is well tolerated in patients with pretreated gynecologic cancers. Short-term disease stabilization was observed. Future studies should assess combinations with other agents, including immunotherapeutics.
Loss of Function of DOCK4 in Myelodysplastic Syndromes Stem Cells is Restored by Inhibitors of DOCK4 Signaling Networks
Authors: Sundaravel Sriram , Kuo Wen-Liang , Jeong Jong Jin , Choudhary Gaurav S. , Gordon-Mitchell Shanisha , Liu Hui , Bhagat Tushar D. , McGraw Kathy L. , Gurbuxani Sandeep , List Alan F. , Verma Amit , Wickrema Amittha 
Published: July 2019

Abstract

Purpose:
Myelodysplastic syndromes (MDS) with deletion of chromosome 7q/7 [-7/(del)7q MDS] is associated with worse outcomes and needs novel insights into pathogenesis. Reduced expression of signaling protein dedicator of cytokinesis 4 (DOCK4) in patients with -7/(del)7q MDS leads to a block in hematopoietic stem cell (HSC) differentiation. Identification of targetable signaling networks downstream of DOCK4 will provide means to restore hematopoietic differentiation in MDS.
Experimental Design: We utilized phosphoproteomics approaches to identify signaling proteins perturbed as a result of reduced expression of DOCK4 in human HSCs and tested their functional significance in primary model systems.

Results:
We demonstrate that reduced levels of DOCK4 lead to increased global tyrosine phosphorylation of proteins in primary human HSCs. LYN kinase and phosphatases INPP5D (SHIP1) and PTPN6 (SHP1) displayed greatest levels of tyrosine phosphorylation when DOCK4 expression levels were reduced using DOCK4-specific siRNA. Our data also found that increased phosphorylation of SHIP1 and SHP1 phosphatases were due to LYN kinase targeting these phosphatases as substrates. Increased migration and impediment of HSC differentiation were consequences of these signaling alterations. Pharmacologic inhibition of SHP1 reversed these functional aberrations in HSCs expressing low DOCK4 levels. In addition, differentiation block seen in DOCK4 haplo-insufficient [-7/(del)7q] MDS was rescued by inhibition of SHP1 phosphatase.

Conclusions:
LYN kinase and phosphatases SHP1 and SHIP1 are perturbed when DOCK4 expression levels are low. Inhibition of SHP1 promotes erythroid differentiation in healthy HSCs and in -7/(del)7q MDS samples with low DOCK4 expression. Inhibitors of LYN, SHP1 and SHIP1 also abrogated increased migratory properties in HSCs expressing reduced levels of DOCK4.
KIT-Dependent and KIT-Independent Genomic Heterogeneity of Resistance in Gastrointestinal Stromal Tumors — TORC1/2 Inhibition as Salvage Strategy
Authors: Mühlenberg Thomas , Ketzer Julia , Heinrich Michael C. , Grunewald Susanne , Marino-Enriquez Adrian , Trautmann Marcel , Hartmann Wolfgang , Wardelmann Eva , Treckmann Jürgen , Worm Karl , Bertram Stefanie , Herold Thomas , Schildhaus Hans-Ulrich , Glimm Hanno , Stenzinger Albrecht , Brors Benedikt , Horak Peter , Hohenberger Peter , Fröhling Stefan , Fletcher Jonathan A. , Bauer Sebastian 
Published: July 2019

Abstract
Sporadic gastrointestinal stromal tumors (GIST), characterized by activating mutations of KIT or PDGFRA, favorably respond to KIT inhibitory treatment but eventually become resistant. The development of effective salvage treatments is complicated by the heterogeneity of KIT secondary resistance mutations. Recently, additional mutations that independently activate KIT-downstream signaling have been found in pretreated patients—adding further complexity to the scope of resistance. We collected genotyping data for KIT from tumor samples of pretreated GIST, providing a representative overview on the distribution and incidence of secondary KIT mutations (n = 80). Analyzing next-generation sequencing data of 109 GIST, we found that 18% carried mutations in KIT-downstream signaling intermediates (NF1/2, PTEN, RAS, PIK3CA, TSC1/2, AKT, BRAF) potentially mediating resistance to KIT inhibitors. Notably, we found no apparent other driver mutations in refractory cases that were analyzed by whole exome/genome sequencing (13/109). Using CRISPR/Cas9 methods, we generated a panel of GIST cell lines harboring mutations in KIT, PTEN, KRAS, NF1, and TSC2. We utilized this panel to evaluate sapanisertib, a novel mTOR kinase inhibitor, as a salvage strategy. Sapanisertib had potent antiproliferative effects in all cell lines, including those with KIT-downstream mutations. Combinations with KIT or MEK inhibitors completely abrogated GIST-survival signaling and displayed synergistic effects. Our isogenic cell line panel closely approximates the genetic heterogeneity of resistance observed in heavily pretreated patients with GIST. With the clinical development of novel, broad spectrum KIT inhibitors, emergence of non-KIT–related resistance may require combination treatments with inhibitors of KIT-downstream signaling such as mTOR or MEK.
Semaphorin 4C Promotes Macrophage Recruitment and Angiogenesis in Breast Cancer
Authors: Yang Jie , Zeng Zhen , Qiao Long , Jiang Xuefeng , Ma Jingjing , Wang Junnai , Ye Shuangmei , Ma Quanfu , Wei Juncheng , Wu Mingfu , Huang Xiaoyuan , Ma Ding , Gao Qinglei 
Published: July 2019

AbstractSemaphorins are a large family of evolutionarily conserved morphogenetic molecules that are associated with repelling axonal guidance. Intriguingly, recent researches indicate that semaphorins are involved in cancer progression. Semaphorin 4C (SEMA4C) has long been considered a neuronal migration gene, but we detected that it is also highly expressed in many malignant human cancers. During an investigation of subcutaneous tumor models, we found that SEMA4C expression promoted tumor growth and progression. We discovered that SEMA4C was involved in maintaining tumor cell self-renewal, likely by regulating the p53 pathway. Inhibiting the expression of endogenous SEMA4C in tumor cells impaired growth and induced senescence and cell-cycle arrest in the G2-phase. In addition, we found that SEMA4C induced the production of angiogenin and colony-stimulating factor-1 (CSF-1) in tumor cells by activating the NF-κB pathway in a plexinB2-dependent manner. In conclusion, SEMA4C expression in breast cancer cells promotes cancer cell proliferation, macrophage recruitment, and angiogenesis. Thus, inhibition of SEMA4C activity may be a novel therapeutic strategy for human breast cancer.Implications:In breast cancer, therapeutic targeting of the SEMA4C pathway may prevent tumor growth, angiogenesis, metastasis, and progression.
HILPDA Regulates Lipid Metabolism, Lipid Droplet Abundance, and Response to Microenvironmental Stress in Solid Tumors
Authors: VandeKopple Matthew J. , Wu Jinghai , Auer Erich N. , Giaccia Amato J. , Denko Nicholas C. , Papandreou Ioanna 
Published: July 2019

Abstract

Accumulation of lipid droplets has been observed in an increasing range of tumors. However, the molecular determinants of this phenotype and the impact of the tumor microenvironment on lipid droplet dynamics are not well defined. The hypoxia-inducible and lipid droplet associated protein HILPDA is known to regulate lipid storage and physiologic responses to feeding conditions in mice, and was recently shown to promote hypoxic lipid droplet formation through inhibition of the rate-limiting lipase adipose triglyceride lipase (ATGL). Here, we identify fatty acid loading and nutrient deprivation–induced autophagy as stimuli of HILPDA-dependent lipid droplet growth. Using mouse embryonic fibroblasts and human tumor cells, we found that genetic ablation of HILPDA compromised hypoxia–fatty acid– and starvation-induced lipid droplet formation and triglyceride storage. Nutrient deprivation upregulated HILPDA protein posttranscriptionally by a mechanism requiring autophagic flux and lipid droplet turnover, independent of HIF1 transactivation. Mechanistically, loss of HILPDA led to elevated lipolysis, which could be corrected by inhibition of ATGL. Lipidomic analysis revealed not only quantitative but also qualitative differences in the glycerolipid and phospholipid profile of HILPDA wild-type and knockout cells, indicating additional HILPDA functions affecting lipid metabolism. Deletion studies of HILPDA mutants identified the N-terminal hydrophobic domain as sufficient for targeting to lipid droplets and restoration of triglyceride storage. In vivo, HILPDA-ablated cells showed decreased intratumoral triglyceride levels and impaired xenograft tumor growth associated with elevated levels of apoptosis.

Implications:
Tumor microenvironmental stresses induce changes in lipid droplet dynamics via HILPDA. Regulation of triglyceride hydrolysis is crucial for cell homeostasis and tumor growth.