bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discriminatory Ability of Lower-Extremity Peak Torque and Rate of Torque Development in the Identification of Older Women With Slow Gait Speed
Authors: Morcelli Mary Hellen , LaRoche Dain Patrick , Crozara Luciano Fernandes , Marques Nise Ribeiro , Hallal Camilla Zamfolini , Gonçalves Mauro , Navega Marcelo Tavella 
Published: February 2018

The aim was to compare torque and rate of torque development of lower limb muscles between older women with functional and slow gait speeds to determine which muscle group is the best predictor of functional gait speed, and to establish strength thresholds needed for functional walking speed. Torque and rate of torque development of hip, knee, and ankle muscles were measured in older women who were divided in 2 groups according to gait speed: slow gait speed (<1.22 m·s−1) and functional gait speed (≥1.22 m·s−1). For each muscle group, 3 maximal isometric contractions were performed, and peak torque and rate of torque development were recorded. Older women with slow gait speed had lower peak torque than older women with functional gait speed for hip extension (28%), knee flexion (15%), knee extension (14%), and plantar flexion (16%) (all Ps < .05). Older women with slow gait speed had lower peak rate of torque development for hip flexion (29%), hip extension (37%), knee flexion (34%), knee extension (33%), and plantar flexion (19%) (all Ps < .05). Knee extension peak rate of torque development and hip extension peak torque were the better predictors of functional gait speed with thresholds of 2.96 N·m·s−1·kg−1 and 1.26 N·m·kg−1, respectively.
The Use of a Wheelchair Propulsion Field Test to Determine Peak Heart Rate in Children and Adolescents With Myelomeningocele
Authors: Leonardi-Figueiredo Marisa Maia , de Souza Mariana Angélica , Lizzi Elisangela Aparecida da Silva , de Oliveira Luciano Fonseca Lemos , Crescencio Julio Cesar , Schwartzmann Pedro Vellosa , Gallo Lourenço , Mattiello-Sverzut Ana Claudia 
Published: February 2018

Purpose: We analyzed the evolution and pattern of heart rate (HR) during the 12-minute wheelchair propulsion field test (WPFT) and compared the peak HR (HRpeak) from the WPFT to the HRpeak obtained in the progressive cardiopulmonary exercise test on arm cranking ergometer (ACT). We aimed to determine if the field test detects the HRpeak consistently and could be used in clinical practice. Methods: Eleven wheelchair-using children and adolescents with myelomeningocele (aged 8–15 y) performed a maximal ACT and a 12-minute WPFT. HR was recorded continuously at rest, during each minute of the tests, and at recovery. Mixed analysis of variance was used to compare the variables at rest and peak. Bland–Altman plot and Lin’s concordance correlation coefficient were used to show agreement between the tests. Results: During minute 2 of the WPFT, participants reached 73%–96% of the HRpeak values recorded in the ACT. From minutes 4 to 12, participants reached HRpeak values ranging 86%–109% of the values recorded in the ACT. There is agreement between the ACT and the WPFT tests. Conclusion: WPFT with minimal duration of 4 minutes may be an alternative tool to obtain HRpeak in children and adolescents with myelomeningocele.
Treatment of Clostridium difficile Infection with a Small-Molecule Inhibitor of Toxin UDP-Glucose Hydrolysis Activity
Authors: Stroke Ilana L. , Letourneau Jeffrey J. , Miller Teresa E. , Xu Yan , Pechik Igor , Savoly Diana R. , Ma Linh , Sturzenbecker Laurie J. , Sabalski Joan , Stein Philip D. , Webb Maria L. , Hilbert David W. 
Published: February 2018

ABSTRACT

Clostridium difficile
infection (CDI) is the leading cause of hospital-acquired infectious diarrhea, with significant morbidity, mortality, and associated health care costs. The major risk factor for CDI is antimicrobial therapy, which disrupts the normal gut microbiota and allows
C. difficile
to flourish. Treatment of CDI with antimicrobials is generally effective in the short term, but recurrent infections are frequent and problematic, indicating that improved treatment options are necessary. Symptoms of disease are largely due to two homologous toxins, TcdA and TcdB, which are glucosyltransferases that inhibit host Rho GTPases. As the normal gut microbiota is an important component of resistance to CDI, our goal was to develop an effective nonantimicrobial therapy. Here, we report a highly potent small-molecule inhibitor (VB-82252) of TcdA and TcdB. This compound inhibits the UDP-glucose hydrolysis activity of TcdB and protects cells from intoxication after challenge with either toxin. Oral dosing of the inhibitor prevented inflammation in a murine intrarectal toxin challenge model. In a murine model of recurrent CDI, the inhibitor reduced weight loss and gut inflammation during acute disease and did not cause the recurrent disease that was observed with vancomycin treatment. Lastly, the inhibitor demonstrated efficacy similar to that of vancomycin in a hamster disease model. Overall, these results demonstrate that small-molecule inhibition of
C. difficile
toxin UDP-glucose hydrolysis activity is a promising nonantimicrobial approach to the treatment of CDI.
24th Annual Midwest Microbial Pathogenesis Conference
Authors: Champion Patricia A. , Shrout Joshua D. 
Published: February 2018

ABSTRACTThe 24th Annual Midwest Microbial Pathogenesis Conference (MMPC) was held at the University of Notre Dame from 25 to 27 August 2017. The conference provided an opportunity for scientists from the Midwest to discuss new advances in microbial pathogenesis, including how pathogens promote disease and how they interact with each other, the microbiome, and the host. We highlight the history of the MMPC, the topics presented at the conference, and the reports in this issue of theJournal of Bacteriology.
Disentangling the determinants of interest and willingness-to-pay for breast cancer susceptibility testing in the general population: a cross-sectional Web-based survey among women of Québec (Canada)
Authors: Blouin-Bougie Jolyane , Amara Nabil , Bouchard Karine , Simard Jacques , Dorval Michel 
Published: February 2018

ObjectivesTo identify common and specific individual factors that favour or impede women’s interest in and willingness-to-pay (WTP) for breast cancer susceptibility testing (BCST) and to identify the most impactful factors on both outcome measures.Design and methodsThis study used a self-administered cross-sectional Web-based questionnaire that included hypothetical scenarios about the availability of a new genetic test for breast cancer.ParticipantsFrench-speaking women of the general population of Québec (Canada), aged between 35 and 69 years, were identified from a Web-based panel (2410 met the selection criteria, 1160 were reached and 1031 completed the survey).MeasuresThe outcomes are the level of interest in and the range of WTP for BCST. Three categories of individual factors identified in the literature were used as potential explanatory factors, that is, demographic, clinical and psychosocial.ResultsDescriptive statistics indicated that the vast majority of sampled women are interested in BCST (90%). Among those, more than half of them are willing-to-pay for such a test (57%). The regression models pointed out several factors associated with both outcomes (eg, age, income, family history, locus of control-powerful others) and marginal effects were used to highlight the most impactful factors for each outcome.ConclusionThe results of this study provide a proxy of the readiness of women of the general population to use and to pay for BCST. They also offer insights for developing inclusive and specific strategies to foster informed decision-making and guide the services offered by health organisations corresponding to women’s preferences and needs.
Multiple barriers to participation for people with psychosocial disability in Dehradun district, North India: a cross-sectional study
Authors: Mathias Kaaren , Pant Hira , Marella Manju , Singh Lawrence , Murthy GVS , Grills Nathan 
Published: February 2018

ObjectivesThis study used a population-based cross-sectional survey to describe the prevalence of psychosocial disability and unmet need for access to services in North India.SettingThis study was conducted in Dehradun district, Uttarakhand, in 2014.ParticipantsA population-based sample of 2441 people over the age of 18 years.Primary outcome measuresThe Rapid Assessment of Disability survey tool identified people with disability and used an adapted version of the Kessler scale to identify those with psychosocial disability. It additionally collected information on socioeconomic variables, access to community services and barriers to participation. Prevalence of psychosocial disability and unmet needs and descriptions of barriers to services were calculated, and multivariable logistic regression was used to assess associations between risk factors and psychosocial disability.ResultsPrevalence of psychosocial disability was 4.8% and 75% of participants with psychological distress also reported comorbid functional impairments. Adjusted ORs for depression of more than two were found for people who were unschooled, unemployed and of moderate or poor socioeconomic status. The unmet need for access to services was significantly higher in every domain for people with psychosocial disability and was more than 25% in the areas of employment, health service access and community consultation. People with psychosocial disability encountered greater barriers in each domain compared with controls.ConclusionsPeople who are poor, uneducated and unemployed are two to four times more likely to have psychosocial disability in Dehradun district. They face unmet needs in accessing community services and perceive negative social attitudes, lack of physical accessibility and lack of information as barriers limiting their participation. Social policy must increase access to education and reduce poverty but additionally ensure action is taken in all community services to increase information, physical accessibility and social inclusion of people with psychosocial and other forms of disability.
The Unfolded Protein Response: A Novel Therapeutic Target for Poor Prognostic BRAF Mutant Colorectal Cancer
Authors: Forsythe Nicholas , Refaat Alaa , Javadi Arman , Khawaja Hajrah , Weir Jessica-Anne , Emam Heba , Allen Wendy L. , Burkamp Frank , Popovici Vlad , Jithesh Puthen V. , Isella Claudio , Labonte Melissa J. , Mills Ian G. , Johnston Patrick G. , Van Schaeybroeck Sandra 
Published: February 2018

Abstract
BRAF V600E mutations occur in ∼10% of colorectal cancer cases, are associated with poor survival, and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT colorectal cancer. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n = 31; validation set: n = 26) colorectal cancer, and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome. These analyses identified the unfolded protein response (UPR) as a novel and druggable pathway associated with the BRAFMT colorectal cancer subgroup with poorest outcome. We also found that oncogenic BRAF drives endoplasmic reticulum (ER) stress and UPR pathway activation through MEK/ERK. Furthermore, inhibition of GRP78, the master regulator of the UPR, using siRNA or small molecule inhibition, resulted in acute ER stress and apoptosis, in particular in BRAFMT colorectal cancer cells. In addition, dual targeting of protein degradation using combined Carfilzomib (proteasome inhibitor) and ACY-1215 (HDAC6-selective inhibitor) treatment resulted in marked accumulation of protein aggregates, acute ER stress, apoptosis, and therapeutic efficacy in BRAFMT in vitro and xenograft models. Mechanistically, we found that the apoptosis following combined Carfilzomib/ACY-1215 treatment is mediated through increased CHOP expression. Taken together, our findings indicate that oncogenic BRAF induces chronic ER stress and that inducers of acute ER stress could be a novel treatment strategy for poor prognostic BRAFMT colorectal cancer. Mol Cancer Ther; 17(6); 1280–90. ©2018 AACR.
Antitumor Activity of Osimertinib, an Irreversible Mutant-Selective EGFR Tyrosine Kinase Inhibitor, in NSCLC Harboring EGFR Exon 20 Insertions
Authors: Floc'h Nicolas , Martin Matthew J. , Riess Jonathan W. , Orme Jonathan P. , Staniszewska Anna D. , Ménard Ludovic , Cuomo Maria Emanuela , O'Neill Daniel J. , Ward Richard A. , Finlay M. Raymond V. , McKerrecher Darren , Cheng Mingshan , Vang Daniel P. , Burich Rebekah A. , Keck James G. , Gandara David R. , Mack Philip C. , Cross Darren A.E. 
Published: February 2018

Abstract
EGFR exon 20 insertions (Ex20Ins) account for 4% to 10% of EGFR activating mutations in non–small cell lung cancer (NSCLC). EGFR Ex20Ins tumors are generally unresponsive to first- and second-generation EGFR inhibitors, and current standard of care for NSCLC patients with EGFR Ex20Ins is conventional cytotoxic chemotherapy. Therefore, the development of an EGFR TKI that can more effectively target NSCLC with EGFR Ex20Ins mutations represents a major advance for this patient subset. Osimertinib is a third-generation EGFR TKI approved for the treatment of advanced NSCLC harboring EGFR T790M; however, the activity of osimertinib in EGFR Ex20Ins NSCLC has yet to be fully assessed. Using CRISPR-Cas 9 engineered cell lines carrying the most prevalent Ex20Ins mutations, namely Ex20Ins D770_N771InsSVD (22%) or Ex20Ins V769_D770InsASV (17%), and a series of patient-derived xenografts, we have characterized osimertinib and AZ5104 (a circulating metabolite of osimertinib) activities against NSCLC harboring Ex20Ins. We report that osimertinib and AZ5104 inhibit signaling pathways and cellular growth in Ex20Ins mutant cell lines in vitro and demonstrate sustained tumor growth inhibition of EGFR-mutant tumor xenograft harboring the most prevalent Ex20Ins in vivo. The antitumor activity of osimertinib and AZ5104 in NSCLC harboring EGFR Ex20Ins is further described herein using a series of patient-derived xenograft models. Together these data support clinical testing of osimertinib in patients with EGFR Ex20Ins NSCLC. Mol Cancer Ther; 17(5); 885–96. ©2018 AACR.
p110α Inhibition Overcomes Stromal Cell–Mediated Ibrutinib Resistance in Mantle Cell Lymphoma
Authors: Guan Jiyu , Huang Dan , Yakimchuk Konstantin , Okret Sam 
Published: February 2018

Abstract
Acquired resistance to cancer drugs is common, also for modern targeted drugs like the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, a new drug approved for the treatment of the highly aggressive and relapsing mantle cell lymphoma (MCL). The tumor microenvironment often impacts negatively on drug response. Here, we demonstrate that stromal cells protect MCL cells from ibrutinib-induced apoptosis and support MCL cell regrowth after drug removal by impairing ibrutinib-mediated downregulation of PI3K/AKT signaling. Importantly, the stromal cell–mediated ibrutinib resistance was overcome in vitro by inhibiting AKT activity using the PI3K catalytic p110α subunit–specific inhibitor BYL719. This was seen both for MCL cell lines and primary MCL cells. Furthermore, inhibition of p110α activity by BYL719 potentiated the ability of ibrutinib to inhibit MCL tumor growth in vivo in a mouse xenograft model. The stromal cell–mediated ibrutinib resistance was found to be due to a direct interaction with MCL cells and involves the integrin VLA-4, as disrupting stromal cell–MCL cell interaction using a VLA-4 blocking antibody abrogated the ibrutinib resistance. This suggests that combined treatment with ibrutinib and a p110α inhibitor, alternatively by disrupting stromal cell–MCL cell interaction, may be a promising therapeutic strategy to overcome stromal cell–mediated ibrutinib resistance in MCL. Mol Cancer Ther; 17(5); 1090–100. ©2018 AACR.
Anti-HER2 scFv-Directed Extracellular Vesicle-Mediated mRNA-Based Gene Delivery Inhibits Growth of HER2-Positive Human Breast Tumor Xenografts by Prodrug Activation
Authors: Wang Jing-Hung , Forterre Alexis V. , Zhao Jinjing , Frimannsson Daniel O. , Delcayre Alain , Antes Travis J. , Efron Bradley , Jeffrey Stefanie S. , Pegram Mark D. , Matin A.C. 
Published: February 2018

Abstract
This paper deals with specific targeting of the prodrug/enzyme regimen, CNOB/HChrR6, to treat a serious disease, namely HER2+ human breast cancer with minimal off-target toxicity. HChrR6 is an improved bacterial enzyme that converts CNOB into the cytotoxic drug MCHB. Extracellular vesicles (EV) were used for mRNA-based HchrR6 gene delivery: EVs may cause minimal immune rejection, and mRNA may be superior to DNA for gene delivery. To confine HChrR6 generation and CNOB activation to the cancer, the EVHB chimeric protein was constructed. It contains high-affinity anti-HER2 scFv antibody (ML39) and is capable of latching on to EV surface. Cells transfected with EVHB-encoding plasmid generated EVs displaying this protein (“directed EVs”). Transfection of a separate batch of cells with the new plasmid, XPort/HChrR6, generated EVs containing HChrR6 mRNA; incubation with pure EVHB enabled these to target the HER2 receptor, generating “EXO-DEPT” EVs. EXO-DEPT treatment specifically enabled HER2-overexpressing BT474 cells to convert CNOB into MCHB in actinomycin D–independent manner, showing successful and specific delivery of HChrR6 mRNA. EXO-DEPTs—but not undirected EVs—plus CNOB caused near-complete growth arrest of orthotopic BT474 xenografts in vivo, demonstrating for the first time EV-mediated delivery of functional exogenous mRNA to tumors. EXO-DEPTs may be generated from patients' own dendritic cells to evade immune rejection, and without plasmids and their potentially harmful genetic material, raising the prospect of clinical use of this regimen. This approach can be used to treat any disease overexpressing a specific marker. Mol Cancer Ther; 17(5); 1133–42. ©2018 AACR.
Impact of Chemical-Induced Mutational Load Increase on Immune Checkpoint Therapy in Poorly Responsive Murine Tumors
Authors: Kuczynski Elizabeth A. , Krueger Janna , Chow Annabelle , Xu Ping , Man Shan , Sundaravadanam Yogi , Miller Jessica K. , Krzyzanowski Paul M. , Kerbel Robert S. 
Published: February 2018

AbstractA recurring historic finding in cancer drug development is encouraging antitumor effects observed in tumor-bearing mice that fail to translate into the clinic. An intriguing exception to this pattern is immune checkpoint therapy, as the sustained tumor regressions observed in subsets of cancer patients are rare in mice. Reasoning that this may be due in part to relatively low mutational loads of mouse tumors, we mutagenized transplantable mouse tumor cell lines EMT-6/P, B16F1, RENCA, CT26, and MC38 in vitro with methylnitro-nitrosoguanidine (MNNG) or ethylmethane sulfonate (EMS) and tested their responsiveness to PD-L1 blockade. Exome sequencing confirmed an increase in somatic mutations by mutagen treatment, an effect mimicked in EMT-6 variants chronically exposed in vivo to cisplatin or cyclophosphamide. Certain mutagenized variants of B16F1, EMT-6/P, CT26, and MC38 (but not RENCA) were more immunogenic than their parents, yet anti-PD-L1 sensitization developed only in some EMT-6/P and B16F1 variants. Treatment response patterns corresponded with changes in immune cell infiltration and especially increases in CD8+ T cells. Chronically cisplatin-exposed EMT-6 variants were also more responsive to anti-PD-L1 therapy. Although tumor PD-L1 expression was upregulated in in vivo chemotherapy-exposed variants, PD-L1 expression levels were not consistently associated with anti-PD-L1 treatment activity across mutagenized or chemotherapy-exposed variants. In summary, mutagenized and more immunogenic mouse tumors were not universally sensitized to PD-L1 blockade. Chemically mutagenized variants may be useful to evaluate the impact of immunologically “hot” or “cold” tumors with a high mutational load, to which certain chemotherapy agents may contribute, on immunotherapy outcomes. Mol Cancer Ther; 17(4); 869–82. ©2018 AACR.
SMARCB1 Deficiency Integrates Epigenetic Signals to Oncogenic Gene Expression Program Maintenance in Human Acute Myeloid Leukemia
Authors: Chatterjee Shankha Subhra , Biswas Mayukh , Boila Liberalis Debraj , Banerjee Debasis , Sengupta Amitava 
Published: February 2018

Abstract
SWI/SNF is an evolutionarily conserved multi-subunit chromatin remodeling complex that regulates epigenetic architecture and cellular identity. Although SWI/SNF genes are altered in approximately 25% of human malignancies, evidences showing their involvement in tumor cell–autonomous chromatin regulation and transcriptional plasticity are limiting. This study demonstrates that human primary acute myeloid leukemia (AML) cells exhibit near complete loss of SMARCB1 (BAF47 or SNF5/INI1) and SMARCD2 (BAF60B) associated with nucleation of SWI/SNFΔ. SMARCC1 (BAF155), an intact core component of SWI/SNFΔ, colocalized with H3K27Ac to target oncogenic loci in primary AML cells. Interestingly, gene ontology (GO) term and pathway analysis suggested that SMARCC1 occupancy was enriched on genes regulating Rac GTPase activation, cell trafficking, and AML-associated transcriptional dysregulation. Transcriptome profiling revealed that expression of these genes is upregulated in primary AML blasts, and loss-of-function studies confirmed transcriptional regulation of Rac GTPase guanine nucleotide exchange factors (GEF) by SMARCB1. Mechanistically, loss of SMARCB1 increased recruitment of SWI/SNFΔ and associated histone acetyltransferases (HAT) to target loci, thereby promoting H3K27Ac and gene expression. Together, SMARCB1 deficiency induced GEFs for Rac GTPase activation and augmented AML cell migration and survival. Collectively, these findings highlight tumor suppressor role of SMARCB1 and illustrate SWI/SNFΔ function in maintaining an oncogenic gene expression program in AML.
Implications: Loss of SMARCB1 in AML associates with SWI/SNFΔ nucleation, which in turn promotes Rac GTPase GEF expression, Rac activation, migration, and survival of AML cells, highlighting SWI/SNFΔ downstream signaling as important molecular regulator in AML. Mol Cancer Res; 16(5); 791–804. ©2018 AACR.
“Ask of the Beasts and They Shall Teach Thee”
Authors: Flack Andrew , Maddeaux Sarah Joy 
Published: February 2018

AbstractPeople have been visiting zoos to look at non-human animals for almost two centuries. They observe a real animal, but what they see in their mind’s eye could be informed by how the animal is represented in the zoo’s guidebooks. Representations are rooted in two ways of looking: one positions the animal as an object of scientific study representative of his or her species, the other turns him or her into an individual animal with a life framed in terms of human experiences. Bristol Zoo Gardens, opened in 1836, offers a rich case study of the value of guidebooks because of its long history and surviving sources. The article begins by highlighting the theoretical approach adopted before applying it by reviewing the objectification and anthropomorphism of different animals over the chronological range of guidebooks. It then interrogates the depiction of gender roles to illuminate this style of representation.