bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acquired Resistance to HER2-Targeted Therapies Creates Vulnerability to ATP Synthase Inhibition
Authors: Gale Molly , Li Yao , Cao Jian , Liu Zongzhi Z. , Holmbeck Marissa A. , Zhang Meiling , Lang Sabine M. , Wu Lizhen , Do Carmo Mariana , Gupta Swati , Aoshima Keisuke , DiGiovanna Michael P. , Stern David F. , Rimm David L. , Shadel Gerald S. , Chen Xiang , Yan Qin 
Published: November 2019

Abstract

Acquired resistance to HER2-targeted therapies occurs frequently in HER2+ breast tumors and new strategies for overcoming resistance are needed. Here, we report that resistance to trastuzumab is reversible, as resistant cells regained sensitivity to the drug after being cultured in drug-free media. RNA-sequencing analysis showed that cells resistant to trastuzumab or trastuzumab + pertuzumab in combination increased expression of oxidative phosphorylation pathway genes. Despite minimal changes in mitochondrial respiration, these cells exhibited increased expression of ATP synthase genes and selective dependency on ATP synthase function. Resistant cells were sensitive to inhibition of ATP synthase by oligomycin A, and knockdown of ATP5J or ATP5B, components of ATP synthase complex, rendered resistant cells responsive to a low dose of trastuzumab. Furthermore, combining ATP synthase inhibitor oligomycin A with trastuzumab led to regression of trastuzumab-resistant tumors in vivo. In conclusion, we identify a novel vulnerability of cells with acquired resistance to HER2-targeted antibody therapies and reveal a new therapeutic strategy to overcome resistance.

Significance:
These findings implicate ATP synthase as a novel potential target for tumors resistant to HER2-targeted therapies.
Heparanase and Chemotherapy Synergize to Drive Macrophage Activation and Enhance Tumor Growth
Authors: Bhattacharya Udayan , Gutter-Kapon Lilach , Kan Tal , Boyango Ilanit , Barash Uri , Yang Shi-Ming , Liu JingJing , Gross-Cohen Miriam , Sanderson Ralph D. , Shaked Yuval , Ilan Neta , Vlodavsky Israel 
Published: November 2019

AbstractThe emerging role of heparanase in tumor initiation, growth, metastasis, and chemoresistance is well recognized, encouraging the development of heparanase inhibitors as anticancer drugs. Unlike the function of heparanase in cancer cells, little attention has been given to heparanase contributed by cells composing the tumor microenvironment. Here, we focused on the cross-talk between macrophages, chemotherapy, and heparanase and the combined effect on tumor progression. Macrophages were markedly activated by chemotherapeutics paclitaxel and cisplatin, evidenced by increased expression of proinflammatory cytokines, supporting recent studies indicating that chemotherapy may promote rather than suppress tumor regrowth and spread. Strikingly, cytokine induction by chemotherapy was not observed in macrophages isolated from heparanase-knockout mice, suggesting macrophage activation by chemotherapy is heparanase dependent. paclitaxel-treated macrophages enhanced the growth of Lewis lung carcinoma tumors that was attenuated by a CXCR2 inhibitor. Mechanistically, paclitaxel and cisplatin activated methylation of histone H3 on lysine 4 (H3K4) in wild-type but not in heparanase-knockout macrophages. Furthermore, the H3K4 presenter WDR5 functioned as a molecular determinant that mediated cytokine induction by paclitaxel. This epigenetic, heparanase-dependent host-response mechanism adds a new perspective to the tumor-promoting functions of chemotherapy, and offers new treatment modalities to optimize chemotherapeutics.Significance:Chemotherapy-treated macrophages are activated to produce proinflammatory cytokines, which are blunted in the absence of heparanase.
IgA-Mediated Killing of Tumor Cells by Neutrophils Is Enhanced by CD47–SIRPα Checkpoint Inhibition
Authors: Treffers Louise W. , ten Broeke Toine , Rösner Thies , Jansen J.H. Marco , van Houdt Michel , Kahle Steffen , Schornagel Karin , Verkuijlen Paul J.J.H. , Prins Jan M. , Franke Katka , Kuijpers Taco W. , van den Berg Timo K. , Valerius Thomas , Leusen Jeanette H.W. , Matlung Hanke L. 
Published: November 2019

Abstract
Therapeutic monoclonal antibodies (mAb), directed toward either tumor antigens or inhibitory checkpoints on immune cells, are effective in cancer therapy. Increasing evidence suggests that the therapeutic efficacy of these tumor antigen–targeting mAbs is mediated—at least partially—by myeloid effector cells, which are controlled by the innate immune-checkpoint interaction between CD47 and SIRPα. We and others have previously demonstrated that inhibiting CD47–SIRPα interactions can substantially potentiate antibody-dependent cellular phagocytosis and cytotoxicity of tumor cells by IgG antibodies both in vivo and in vitro. IgA antibodies are superior in killing cancer cells by neutrophils compared with IgG antibodies with the same variable regions, but the impact of CD47–SIRPα on IgA-mediated killing has not been investigated. Here, we show that checkpoint inhibition of CD47–SIRPα interactions further enhances destruction of IgA antibody–opsonized cancer cells by human neutrophils. This was shown for multiple tumor types and IgA antibodies against different antigens, i.e., HER2/neu and EGFR. Consequently, combining IgA antibodies against HER2/neu or EGFR with SIRPα inhibition proved to be effective in eradicating cancer cells in vivo. In a syngeneic in vivo model, the eradication of cancer cells was predominantly mediated by granulocytes, which were actively recruited to the tumor site by SIRPα blockade. We conclude that IgA-mediated tumor cell destruction can be further enhanced by CD47–SIRPα checkpoint inhibition. These findings provide a basis for targeting CD47–SIRPα interactions in combination with IgA therapeutic antibodies to improve their potential clinical efficacy in tumor patients.
Sphingosine-1-Phosphate Receptor Modulator, FTY720, Improves Diastolic Dysfunction and Partially Reverses Atrial Remodeling in a Tm-E180G Mouse Model Linked to Hypertrophic Cardiomyopathy
Authors: Ryba David M. , Warren Chad M. , Karam Chehade N. , Davis Robert T. , Chowdhury Shamim A.K. , Alvarez Manuel G. , McCann Maximilian , Liew Chong Wee , Wieczorek David F. , Varga Peter , Solaro R. John , Wolska Beata M. 
Published: November 2019

Background:
Hypertrophic cardiomyopathy (HCM) is a genetic cardiovascular disorder, primarily involving mutations in sarcomeric proteins. HCM patients present with hypertrophy, diastolic dysfunction, and fibrosis, but there is no specific treatment. The sphingosine-1-phosphate receptor modulator, FTY720/fingolimod, is approved for treatment of multiple sclerosis. We hypothesize that modulation of the sphingosine-1-phosphate receptor by FTY720 would be of therapeutic benefit in sarcomere-linked HCM.

Methods:

We treated mice with an HCM-linked mutation in tropomyosin (Tm-E180G) and nontransgenic littermates with FTY720 or vehicle for 6 weeks. Compared with vehicle-treated, FTY720-treated Tm-E180G mice had a significant reduction in left atrial size (1.99±0.19 [n=7] versus 2.70±0.44 [n=6] mm;
P
<0.001) and improvement in diastolic function (E/A ratio: 2.69±0.38 [n=7] versus 5.34±1.19 [n=6];
P
=0.004) as assessed by echocardiography.

Results:

Pressure-volume relations revealed significant improvements in the end-diastolic pressure volume relationship, relaxation kinetics, preload recruitable stroke work, and ejection fraction. Detergent-extracted fiber bundles revealed a significant decrease in myofilament Ca
2+
-responsiveness (pCa
50
=6.15±0.11 [n=13] versus 6.24±0.06 [n=14];
P
=0.041). We attributed these improvements to a downregulation of S-glutathionylation of cardiac myosin binding protein-C in FTY720-treated Tm-E180G mice and reduction in oxidative stress by downregulation of NADPH oxidases with no changes in fibrosis.

Conclusions:

This is the first demonstration that modulation of S1PR results in decreased myofilament-Ca
2+
-responsiveness and improved diastolic function in HCM. We associated these changes with decreased oxidative modification of myofilament proteins via downregulation of NOX2. Our data support the hypothesis that modification of sphingolipid signaling may be a novel therapeutic approach in HCM.
Clinical Effectiveness of Cardiac Noninvasive Diagnostic Testing in Patients Discharged From the Emergency Department for Chest Pain
Authors: Roifman Idan , Han Lu , Koh Maria , Wijeysundera Harindra C. , Austin Peter C. , Douglas Pamela S. , Ko Dennis T. 
Published: November 2019

Background
More than 4 million cardiac noninvasive diagnostic tests are performed annually in the United States. However, questions remain regarding their effectiveness in improving clinical outcomes. We sought to evaluate whether noninvasive diagnostic tests were associated with lower rates of myocardial infarction or cardiovascular death when compared with no testing.

Methods and Results

We performed a retrospective, population‐based cohort study of adults evaluated for chest pain and discharged home from an emergency department in Ontario, Canada. Propensity score matching was employed to reduce confounding between the testing and nontesting groups. There were 370 863 patients evaluated in our cohort. Rates of the composite outcome were low for both groups after propensity‐score matching (0.29% and 0.78% for the nontesting group at 90 days and 1 year, respectively, and 0.34% and 0.68% for the noninvasive diagnostic test group at 90 days and 1 year respectively). Over 1 year, patients undergoing noninvasive diagnostic testing had a small but statistically significant lower hazard of developing the composite outcome of myocardial infarction or cardiovascular mortality (hazard ratio, 0.87; 95%
CI
, 0.78–0.96 [
P
<0.01]), which appears to be driven by the high‐risk subgroup (hazard ratio, 0.75; 95%
CI
, 0.61–0.92 [
P
<0.01]).

Conclusions
We report a lower observed rate of the composite outcome of cardiovascular death or myocardial infarction associated with noninvasive diagnostic testing following evaluation for chest pain in the emergency department. This lower rate was driven by the high‐risk subgroup. These results suggest that risk‐based testing should be considered for patients discharged from the emergency department for chest pain.
Caridina biyiga sp. nov., a new freshwater shrimp (Crustacea: Decapoda: Atyidae) from Leichhardt Springs, Kakadu National Park, Australia, based on morphological and molecular data, with a preliminary illustrated key to Northern Territory Caridina
Authors: SHORT JOHN W. , PAGE TIMOTHY J. , HUMPHREY CHRISTOPHER L. 
Published: November 2019

Caridina biyiga sp. nov. is described from Leichhardt Springs, Kakadu National Park, Northern Territory, Australia, based on morphological and molecular data. The new species is highly distinctive among its congeners in having the dactylus of pereiopod 5 similar to the dactyli of pereiopods 3–4 and lacking the comb-like row of spiniform setae typical of the genus. The branchial formula is also distinctive for the genus in lacking an arthrobranch at the base of pereiopod 1 and in having a vestigial epipod on maxilliped 1. Despite the distinctive morphology of the new species, the molecular data did not provide strong support for the recognition of a new genus. Phylogenetic analyses of Australian Caridina using the mitochondrial 16S rDNA gene fragment placed the new species in a well-supported clade containing at least one typical species of Caridina. Within this clade, referred to as the ‘thermophila’ group, Kimura 2-parameter (K2P) genetic distances of 16S rDNA between the new species and sister taxa ranged from 5.1–6.0%. Analyses using the mitochondrial 3’ COI gene fragment from species of the ‘thermophila’ group yielded K2P genetic distances between the new species and its sister taxa ranging from 10.4–15.1%. A preliminary illustrated key to Northern Territory Caridina is provided. The conservation significance of Leichhardt Springs and its aquatic fauna are also briefly discussed.
El Niño–Related Tropical Land Surface Water and Energy Response in MERRA-2
Authors: Bosilovich Michael G. , Robertson Franklin R. , Stackhouse Paul W. 
Published: November 2019

AbstractAlthough El Niño events each have distinct evolutionary character, they typically provide systematic large-scale forcing for warming and increased drought frequency across the tropical continents. We assess this response in the Modern-Era Retrospective Analysis for Research and Applications, version 2 (MERRA-2), reanalysis and in a 10-member-model Atmospheric Model Intercomparison Project (AMIP) ensemble. The lagged response (3–4 months) of mean tropical land temperature to El Niño warming in the Pacific Ocean is well represented. MERRA-2 reproduces the patterns of precipitation in the tropical regions, and the AMIP ensemble reproduces some regional responses that are similar to those observed and some regions that are not simulating the response well. Model skill is dependent on event forcing strength and temporal proximity to the peak of the sea surface warming. A composite approach centered on maximum Niño-3.4 SSTs and lag relationships to energy fluxes and transports is used to identify mechanisms supporting tropical land warming. The composite necessarily moderates weather-scale variability of the individual events while retaining the systematic features across all events. We find that reduced continental upward motions lead to reduced cloudiness and more shortwave radiation at the surface, as well as reduced precipitation. The increased shortwave heating at the land surface, along with reduced soil moisture, leads to warmer surface temperature, more sensible heating, and warming of the lower troposphere. The composite provides a broad picture of the mechanisms governing the hydrologic response to El Niño forcing, but the regional and temporal responses can vary substantially for any given event. The 2015/16 El Niño, one of the strongest events, demonstrates some of the forced response noted in the composite, but with shifts in the evolution that depart from the composite, demonstrating the limitations of the composite and individuality of El Niño.
Comparing mismatch strategies for patients being considered for ischemic stroke tenecteplase trials
Authors: Bivard Andrew , Huang Xuya , Levi Christopher R , Campbell Bruce CV , Cheripelli Bharath K , Chen Chushuang , Kalladka Dheeraj , Moreton Fiona C , Ford Ian , Davis Stephen M , Donnan Geoffrey A , Muir Keith W , Parsons Mark W 
Published: November 2019

Background Currently there are multiple variations of imaging-based patient selection mismatch methods in ischemic stroke. In the present study, we sought to compare the two most common mismatch methods and identify if there were different effects on the outcome of a randomized clinical trial depending on the mismatch method used. Aims Investigate the effect of clinical and imaging-based mismatch criteria on patient outcomes of a pooled cohort from randomized trials of intravenous tenecteplase versus alteplase. Methods Baseline clinical and imaging scores were used to categorize patients as meeting either the DAWN mismatch (baseline NIHSS ≥ 10, and age cut-offs for ischemic core volume) or DEFUSE 2 mismatch criteria (mismatch volume > 15 mL, mismatch ratio > 1.8 and ischemic core < 70 mL). We then investigated whether tenecteplase-treated patients had favorable odds of less disability (on modified Rankin scale, mRS) compared to those treated with alteplase, for clinical and imaging mismatch, respectively. Results From 146 pooled patients, 71 received alteplase and 75 received tenecteplase. The overall pooled group did not show improved patient outcomes when treated with tenecteplase (mRS 0-1 OR 1.77, 95% CI 0.89–3.51, p = 0.102) compared with alteplase. A total of 39 (27%) patients met both clinical and imaging mismatch criteria, 25 (17%) patients met only imaging criteria, 36 (25%) met only clinical mismatch criteria and, finally, 46 (31%) did not meet either of imaging or mismatch criteria. Patients treated with tenecteplase had more favorable outcomes when they met either imaging mismatch (mRS 0–1, OR 2.33, 95% CI 1.13–5.94, p = 0.032) or clinical mismatch criteria (mRS 0–1, OR 2.15, 95% CI 1.142, 8.732, p = 0.027) but with differing proportions. Conclusion Target mismatch selection was more inclusive and exhibited in a larger treatment effect between tenecteplase and alteplase.
Identifying the World Health Organization’s fifth moment for hand hygiene: Infection prevention in the operating room
Authors: Smith Fiona , Lee Karen , Binnie-McLeod Eleanor , Higgins Mark , Irvine Elizabeth , Henderson Angela , Orr Ann , Clark Fiona , Spence Joanne 
Published: November 2019

Background: The World Health Organization have designed the fifth of their ‘5 moments’ for hand hygiene to account for microbial transfer from patients to equipment in a narrow area around that patient, known as the patient zone. The study was prompted by emerging local confusion about application of the patient zone in the operating room (OR). Aim/Objectives: In two phases, we aimed to create a ‘5 moments’ style poster displaying an OR patient zone: phase 1, quantify equipment, in direct contact with the patient and, touched by non-scrubbed staff immediately after touching the patient; and phase 2, categorise equipment identified in phase 1 into patient zone and healthcare zone. An objective is to produce a ‘5 moments’ poster for the OR. Methods: The first phase used non-participant direct overt observation. In phase 2, phase 1 data were collaboratively assigned to patient zone or healthcare zone. Photography and graphic design were used to produce the OR ‘5 moments’ poster. Results: In 11 full-length surgeries, 20 pieces of equipment were in direct contact with the patient and 57 pieces of equipment were touched. In phase 2, a ‘5 moments’ poster showing an OR patient zone was designed. Discussion: Content of the patient zone was identified and displayed in a novel resource. Having shared understanding of the patient zone has potential to sustain hand hygiene compliance and equipment cleaning in the OR. Conclusion: Limitations in methods were balanced by collaboration with frontline staff. The study has been used as a teaching tool in the OR and similar settings.
A practical genome-enabled legitimacy assay for oil palm breeding and seed production
Authors: Teh Chee-Keng , Lee Heng-Leng , Abidin Hafiza , Ong Ai-Ling , Mayes Sean , Chew Fook-Tim , Appleton David 
Published: November 2019

Abstract

Background
Legitimacy in breeding and commercial crop production depends on optimised protocols to ensure purity of crosses and correct field planting of material. In oil palm, the presence of three fruit forms permits these assumptions to be tested, although only after field planting. The presence of incorrect fruit forms in a cross is a clear sign of illegitimacy. Given that tenera forms produce 30% more oil for the same weight of fruit as dura, the presence of low levels of dura contamination can have major effect during the economic lifespan of an oil palm, which is around 25 years. We evaluated two methods for legitimacy test 1) The use of SHELL markers to the gene that determines the shell-thickness trait 2) The use of SNP markers, to determine the legitimacy of the cross.

Results
Our results indicate that the SHELL markers can theoretically reduce the major losses due to dura contamination of tenera planting material. However, these markers cannot distinguish illegitimate tenera, which reduces the value of having bred elite tenera for commercial planting and in the breeding programme, where fruit form is of limited utility, and incorrect identity could lead to significant problems. We propose an optimised approach using SNPs for routine quality control.

Conclusions
Both dura and tenera contamination can be identified and removed at or before the nursery stage. An optimised legitimacy assay using SNP markers coupled with a suitable sampling scheme is now ready to be deployed as a standard control for seed production and breeding in oil palm. The same approach will also be an effective solution for other perennial crops, such as coconut and date palm.
Low free triiodothyronineis predicts worsen neurological outcome of patients with acute ischemic stroke: a retrospective study with bioinformatics analysis
Authors: Zhang Shanchao , Zhao Xia , Xu Shan , Yuan Jing , Si Zhihua , Yang Yang , Qiao Shan , Xu Xuxu , Wang Aihua 
Published: November 2019

AbstractBackgroudPatients with acute ischemic stroke (AIS) often experience low serum free triiodothyronine (FT3), but the association of low FT3 with stroke severity, subtype and prognosis has not yet been thoroughly studied, and the molecular events underlying these clinical observation were also unclear.MethodsWe retrospectively collected 221 cases of AIS and 182 non-AIS cases with detailed clinical data from our department. FT3 concentrations were measured on admission to predict functional outcome within 3 months using multivariable models adjusted for other risk factors. Receiver operating characteristic (ROC) curves were calculated to define the best cutoff value of FT3 of stroke severity, subtypes and neurological outcome. Gene set enrichment, pathway mapping and network analyses of deferentially expressed genes (DEGs) were performed.ResultsFT3 was significantly decreased in AIS patients with National Institutes of Health Stroke Scale (NIHSS) > 3 and 3-months modified Rankin Scale (mRS) > 2. The cut-off value of FT3 for NIHSS on admission was 4.30 pmol/L. Also, FT3 level was significantly lower in large artery atherosclerosis (LAA) group and cardioembolism (CE) group than that in small vessel occlusion (SVO). FT3 value served as an independent predictor for neurological outcomes for which the cut-off value of FT3 was 4.38 pmol/l. Gene ontology (GO) analysis showed that the biological function of DEGs was mainly enriched in multicellur organism, neuron differentiation and cellular response to hypoxia. The cellular components were involved in extracelluar region, exosome and matrix, and the molecular functions were transcriptional activator activity, DNA binding and nuclear hormone receptor binding. Signal pathways analysis was indicative of neuroactive ligand-receptor interaction, thyroid hormone signaling pathway, and protein digestion and absorption these DEGs were involved in. Six related gene were identified as hubs from the protein-protein interaction (PPI) networks. Three modules were selected from PPI, of which MMP4, ADRA2C and EIF3E were recognized as the seed genes.ConclusionsLow FT3 value on admission was associated with stroke severity, subtype and prognosis. In addition, DEGs identified from bioinformatics analysis are likely to be candidates for elucidating clinical outcomes with low FT3, and provide us with therapeutic targets for improving stroke prognosis.