bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of TGFBR1, TGFBR2, TGFBR3, ACVR1B and ACVR2B is altered in ovaries of cows with cystic ovarian disease
Authors: Matiller Valentina , Hein Gustavo J. , Stassi Antonela F. , Angeli Emmanuel , Belotti Eduardo M. , Ortega Hugo H. , Rey Florencia , Salvetti Natalia R. 
Published: August 2018

ContentsThe objective of this study was to examine the expression of transforming growth factor beta receptor (TGFBR)1, TGFBR2, TGFBR3, activin receptor (ACVR)1B and ACVR2B in ovaries of cows with cystic ovarian disease (COD). The expression of the selected receptors was determined by immunohistochemistry in sections of ovaries from cows with ACTH‐induced and spontaneous COD. Expression of TGFBR1 and TGFBR3 was higher in granulosa cells of cysts from cows with spontaneous COD than in tertiary follicles from the control group. Additionally, TGFBR3 expression was higher in granulosa cells of cysts from cows with ACTH‐induced COD than in those from the control group and lower in theca cells of spontaneous and ACTH‐induced cysts than in tertiary control follicles. There were no changes in the expression of TGFBR2. ACVR1B expression was higher in granulosa cells of tertiary follicles of cows with spontaneous COD than in the control group, whereas ACVR2B expression was higher in cysts of the spontaneous COD group than in tertiary follicles from the control group. The alterations here detected, together with the altered expression of the ligands previously reported, indicate alterations in the response of the ligands in the target cells, modifying their actions at cellular level.
Metabolic and performance‐related consequences of exercising at and slightly above MLSS
Authors: Iannetta Danilo , Inglis Erin Calaine , Fullerton Christopher , Passfield Louis , Murias Juan M. 
Published: August 2018

Exercising at the maximal lactate steady state (MLSS) results in increased but stable metabolic responses. We tested the hypothesis that even a slight increase above MLSS (10 W), by altering the metabolic steady state, would reduce exercise performance capacity. Eleven trained men in our study performed: one ramp‐incremental tests; two to four 30‐minute constant‐load cycling exercise trials to determine the PO at MLSS (MLSSp), and ten watts above MLSS (MLSSp+10), which were immediately followed by a time‐to‐exhaustion test; and a time‐to‐exhaustion test with no‐prior exercise. Pulmonary O2 uptake V.O2) and blood lactate concentration ([La−]b) as well as local muscle O2 extraction ([HHb]) and muscle activity (EMG) of the vastus lateralis (VL) and rectus femoris (RF) muscles were measured during the testing sessions. When exercising at MLSSp+10, although V.O2 was stable, there was an increase in ventilatory responses and EMG activity, along with a non‐stable [La−]b response (P < 0.05). The [HHb] of VL muscle achieved its apex at MLSSp with no additional increase above this intensity, whereas the [HHb] of RF progressively increased during MLSSp+10 and achieved its apex during the time‐to‐exhaustion trials. Time‐to‐exhaustion performance was decreased after exercising at MLSSp (37.3 ± 16.4%) compared to the no‐prior exercise condition, and further decreased after exercising at MLSSp+10 (64.6 ± 6.3%) (P < 0.05). In summary, exercising for 30 min slightly above MLSS led to significant alterations of metabolic responses which disproportionately compromised subsequent exercise performance. Furthermore, the [HHb] signal of VL seemed to achieve a “ceiling” at the intensity of exercise associated with MLSS.
Ameliorating acidity of an extensively‐managed permanent pasture soil
Authors: Norton M. R. , Garden D. L. , Orchard B. A. , Armstrong P. 
Published: August 2018

AbstractAcid soil amelioration was measured annually over an 11 year experiment. Lime, and superphosphate were surface‐applied under combinations of three rates of lime, viz. nil, lime to raise pHCa of 0–10 cm to 5.0 (low rate) and 5.5 (high rate) respectively, two rates of superphosphate (125 kg/ha every 2 to 3 yr, 250 kg/ha/yr) and two sheep stocking rates. Soils were sampled at 0–2.5, 2.5–5, 5–7.5, 7.5–10, 10–15 and 15–20 cm. Soil pH stratification developed after lime application. By 11 yr lime had not raised pHCa to either 5.0 or 5.5 in the 5–10 cm profile. However, pHCa >5.0 or >5.5 were observed in the 0–5 cm profile. Under high P, low lime application, soil pHCa was higher in the 0–2.5 cm profile at low stocking rate. Effects of applied lime on pHCa declined with time and depth under low lime and the relationship with Alex which increased as pHCa declined, was modelled. A rarely reported relationship showed that as soil C increased the apparent solubility of Al decreased. At the lowest pHCa considered, there was a strong negative association between Alex and total C, becoming weaker with positive pHCa increments. Higher P rates increased pHCa under low lime contrasting with lesser effects on pHCa under low P at the same lime rate. Slow and limited lime movement means that farmers growing acid sensitive plants must apply lime early enough and at rates and frequencies sufficient to ensure downward movement.
Effects of clotrimazole troches on tacrolimus dosing in heart transplant recipients
Authors: Laub Melissa R. , Crow Stacy A. , Personett Heather A. , Dierkhising Ross , Boilson Barry , Razonable Raymund 
Published: August 2018

AbstractBackgroundTacrolimus is a cornerstone of immunosuppression after transplantation but is highly susceptible to changes from interacting variables and has a narrow therapeutic index. Clotrimazole troches are commonly used as a non‐systemic antifungal to prevent oral candidiasis. Studies suggest that clotrimazole troches, though minimally absorbed systemically, may affect tacrolimus concentrations by inhibition of metabolic enzyme activity in the intestines. However, the magnitude of the impact of clotrimazole on tacrolimus dosing requirements to maintain goal levels is not well described.MethodsTo assess this, tacrolimus dose adjustments and trough concentrations were retrospectively examined in 95 heart transplant recipients before and after the discontinuation of clotrimazole.ResultsThe median percent tacrolimus dose change was an increase of 66.7% (IQR 28.6%, 100%) after clotrimazole discontinuation, and the median trough concentration percent change from baseline to the first trough after clotrimazole discontinuation (in the absence of a dose change) was −42.5% (IQR −52.3%, −30.9%). Five cases of allograft rejection were observed.ConclusionIn conclusion, clotrimazole troches exert a meaningful interaction with tacrolimus that requires close monitoring and dose adjustment. The data from this single‐center study provide novel information that could guide providers on the degree of tacrolimus dose adjustment needed when discontinuing clotrimazole prophylaxis after heart transplantation.
Internal iliac artery transposition for vascular reconstruction in a patient with life-threatening iatrogenic common iliac artery injury
Authors: Mishra Biplab , Joshi Mohit Kumar , Gupta Babita , Farooque Kamran 
Published: August 2018

Major vascular injury during surgery is life threatening and can be a nightmare for any surgeon.We share our experience of a 42-year-old woman where right common iliac artery and both common iliac veins were accidentally injured during lumbar discectomy leading to haemorrhagic shock. Patient was resuscitated and explored. A 4 cm segment of right common iliac artery was found lacerated along with perforations of both iliac veins. Proximal segment of internal iliac artery was mobilised quickly and vascular continuity was restored by end-to-end anastomosis of this segment to the proximal segment of common iliac artery after excising the damaged segment. Iliac veins were repaired primarily. Patient made an uneventful recovery. We share this technique as it was found expeditious and effective and may benefit surgeons working in this field.
Current research priorities for UK occupational physicians and occupational health researchers: a modified Delphi study
Authors: Lalloo Drushca , Demou Evangelia , Smedley Julia , Madan Ira , Asanati Kaveh , Macdonald Ewan Beaton 
Published: August 2018

ObjectivesStudies identifying national occupational health (OH) research priorities have been conducted in several countries to establish where OH research should be focused and where funding should be targeted. However, the UK findings are now over 20 years old, and OH practice is continuously evolving. The aim of this study was to identify current research priorities for UK occupational physicians (OPs) and occupational health researchers (OHRs).MethodsCurrent research priorities in OH were identified using a modified Delphi technique. This was conducted in two rounds to achieve consensus. Research priorities were rated, and then ranked using questionnaires developed from expert panel discussions, key research topics identified from the medical literature and participant feedback. Overall and intergroup comparisons were completed for the ranking scores.ResultsConsensus among OPs and OHRs was high with almost all (9/10) primary domains rated as ‘very important’ or ‘absolutely necessary’ by more than 54% of respondents. The research priority areas ranked highest were jointlyeconomic evaluation/cost effectiveness studiesanddisability managementfollowed byoccupational disease/injury/illness. Occupational health policywas ranked lowest aftersickness absence managementandhealth promotion. The secondary domain analysis identified priority emphasis on mental health and psychosocial hazards within the workplace and the need to further develop evidence-based guidance for clinical OH practice.ConclusionsWe identified the current research priorities for UK OPs and OHRs. The findings will inform future national OH research strategy and support research that addresses important knowledge gaps within OH and other interdisciplinary specialties.
Quasi-flat representations of uniform groups and quantum groups
Authors: Banica Teodor , Chirvasitu Alexandru 
Published: August 2018

Given a discrete group [Formula: see text] and a number [Formula: see text], a unitary representation [Formula: see text] is called quasi-flat when the eigenvalues of each [Formula: see text] are uniformly distributed among the [Formula: see text]th roots of unity. The quasi-flat representations of [Formula: see text] form altogether a parametric matrix model [Formula: see text]. We compute here the universal model space [Formula: see text] for various classes of discrete groups, notably with results in the case where [Formula: see text] is metabelian. We are particularly interested in the case where [Formula: see text] is a union of compact homogeneous spaces, and where the induced representation [Formula: see text] is stationary in the sense that it commutes with the Haar functionals. We present several positive and negative results on this subject. We also discuss similar questions for the discrete quantum groups, proving a stationarity result for the discrete dual of the twisted orthogonal group [Formula: see text].
Soy Isoflavone Intake and Bladder Cancer Risk in Japan: From the Takayama Study
Authors: Wada Keiko , Tsuji Michiko , Tamura Takashi , Konishi Kie , Goto Yuko , Mizuta Fumi , Koda Sachi , Uji Takahiro , Hori Akihiro , Tanabashi Shinobu , Matsushita Shogen , Tokimitsu Naoki , Nagata Chisato 
Published: August 2018

Abstract
Background: There is growing evidence suggesting that soy isoflavones play a protective role in the development of cancer. However, few epidemiological studies have investigated the association between soy isoflavone intake and bladder cancer.
Methods: We evaluated the associations of soy and isoflavone intakes with bladder cancer incidence in a population-based prospective study in Japan. Subjects were 14,233 men and 16,584 women age 35 years or older in September 1992. Soy and isoflavone intakes were assessed via a validated food-frequency questionnaire, while controlling for total energy intake. Cancer incidence was mainly confirmed through regional population-based cancer registries. Bladder cancer was defined as code C67 according to the International Classification of Diseases and Health Related Problems, 10th Revision.
Results: During mean follow-up of 13.6 years, 120 men and 41 women had developed bladder cancer. After adjustments for multiple confounders, compared with the lowest quartile of soy food intake, the estimated hazard ratios for the second, third, and highest quartiles of soy food intake were 0.74, 0.52, and 0.55, respectively, in men (P-trend: 0.023). The corresponding values were 0.60, 0.75, and 0.64, respectively, in women (P-trend: 0.43). Similar inverse associations were observed between isoflavone intake and bladder cancer risk.
Conclusions: A significant decreased risk of bladder cancer was observed among men who had higher intakes of total soy and isoflavones.
Impact: Our finding on the potential benefit of consuming soy foods against bladder cancer is promising and warrants further studies. Cancer Epidemiol Biomarkers Prev; 27(11); 1371–5. ©2018 AACR.
Phase II Study of Iniparib with Concurrent Chemoradiation in Patients with Newly Diagnosed Glioblastoma
Authors: Blakeley Jaishri O. , Grossman Stuart A. , Chi Andrew S. , Mikkelsen Tom , Rosenfeld Myrna R. , Ahluwalia Manmeet S. , Nabors L. Burt , Eichler April , Ribas Ignacio Garcia , Desideri Serena , Ye Xiaobu 
Published: August 2018

Abstract

Purpose:
Iniparib is a purported prodrug causing cell death through intracellular conversion to nitro radical ions. We assessed the efficacy and safety of iniparib with standard radiotherapy and temozolomide in patients with newly diagnosed glioblastoma (GBM).

Patients and Methods:
Adults meeting eligibility criteria were enrolled in this prospective, single-arm, open-label multi- institution phase II trial with median overall survival (mOS) compared with a historical control as the primary objective. A safety run-in component of radiotherapy + temozolomide + iniparib (n = 5) was followed by an efficacy study (n = 76) with the recommended phase II doses of iniparib (8.0 mg/kg i.v. twice/week with radiotherapy + daily temozolomide followed by 8.6 mg/kg i.v. twice/week with 5/28-day temozolomide).

Results:
The median age of the 81 evaluable participants was 58 years (63% male). Baseline KPS was ≥ 80% in 87% of participants. The mOS was 22 months [95% confidence interval (CI), 17–24] and the HR was 0.44 (95% CI, 0.35–0.55) per-person-year of follow-up. The 2- and 3-year survival rates were 38% and 25%, respectively. Treatment-related grade 3 adverse events (AEs) occurred in 27% of patients; 9 patients had AEs requiring drug discontinuation including infusion-related reaction, rash, gastritis, increased liver enzymes, and thrombocytopenia.

Conclusions:
Iniparib is well tolerated with radiotherapy and temozolomide in patients with newly diagnosed GBM at up to 17.2 mg/kg weekly. The primary objective of improved mOS compared with a historical control was met, indicating potential antitumor activity of iniparib in this setting. Dosing optimization (frequency and sequence) is needed prior to additional efficacy studies.
RAB37 Hypermethylation Regulates Metastasis and Resistance to Docetaxel-Based Induction Chemotherapy in Nasopharyngeal Carcinoma
Authors: Li Yingqin , Yang Xiaojing , Du Xiaojing , Lei Yuan , He Qingmei , Hong Xiaohong , Tang Xinran , Wen Xin , Zhang Panpan , Sun Ying , Zhang Jian , Wang Yaqin , Ma Jun , Liu Na 
Published: August 2018

Abstract

Purpose:
Epigenetic alterations play important roles in metastasis and drug resistance through gene regulation. However, the functional features and molecular mechanisms of epigenetic changes remain largely unclear in nasopharyngeal carcinoma (NPC) metastasis.

Experimental Design:
Gene regulatory network analysis was used to identify metastatic-specific dysregulated genes between normal and NPC tissues and the expression was validated in published Gene-Expression Omnibus data set. The regulatory and functional role of RAB37 downregulation was examined in NPC and was validated in vitro and in vivo, and downstream target of RAB37 was explored. The clinical value of RAB37 methylation was evaluated in NPC metastasis and chemosensitivity.

Results:
We identified RAB37 as a specific hypermethylated gene that is most commonly downregulated in NPC. Moreover, RAB37 downregulation was attributed to hypermethylation of its promoter and was significantly associated with metastasis- and docetaxel chemoresistance-related features in NPC. Ectopic RAB37 overexpression suppressed NPC cell metastasis and enhanced chemosensitivity to docetaxel. Mechanistically, RAB37 colocalized with TIMP2, regulated TIMP2 secretion, inhibited downstream MMP2 activity, and consequently altered NPC cell metastasis. Furthermore, RAB37 hypermethylation was correlated with poor clinical outcomes in patients with NPC. We developed a prognostic model based on RAB37 methylation and N stage that effectively predicted an increased risk of distant metastasis and a favorable response to docetaxel-containing induction chemotherapy (IC) in NPC patients.

Conclusions:
This study shows that RAB37 hypermethylation is involved in NPC metastasis and chemoresistance, and that our prognostic model can identify patients who are at a high risk of distant metastasis and might benefit from for docetaxel IC.
SLC46A3 as a Potential Predictive Biomarker for Antibody–Drug Conjugates Bearing Noncleavable Linked Maytansinoid and Pyrrolobenzodiazepine Warheads
Authors: Kinneer Krista , Meekin John , Tiberghien Arnaud C. , Tai Yu-Tzu , Phipps Sandrina , Kiefer Christine Mione , Rebelatto Marlon C. , Dimasi Nazzareno , Moriarty Alyssa , Papadopoulos Kyriakos P. , Sridhar Sriram , Gregson Stephen J. , Wick Michael J. , Masterson Luke , Anderson Kenneth C. , Herbst Ronald , Howard Philip W. , Tice David A. 
Published: August 2018

AbstractPurpose:Antibody–drug conjugates (ADC) utilizing noncleavable linker drugs have been approved for clinical use, and several are in development targeting solid and hematologic malignancies including multiple myeloma. Currently, there are no reliable biomarkers of activity for these ADCs other than presence of the targeted antigen. We observed that certain cell lines are innately resistant to such ADCs, and sought to uncover the underlying mechanism of resistance.Experimental Design:The expression of 43 lysosomal membrane target genes was evaluated in cell lines resistant to ADCs bearing the noncleavable linker, pyrrolobenzodiazepine payload SG3376, in vitro. The functional relevance of SLC46A3, a lysosomal transporter of noncleavable ADC catabolites whose expression uniquely correlated with SG3376 resistance, was assessed using EPHA2-, HER2-, and BCMA-targeted ADCs and isogenic cells overexpressing or genetically inactivated for SLC46A3. SLC46A3 expression was also examined in patient-derived xenograft and in vitro models of acquired T-DM1 resistance and multiple myeloma bone marrow samples by RT-PCR.Results:Loss of SLC46A3 expression was found to be a mechanism of innate and acquired resistance to ADCs bearing DM1 and SG3376. Sensitivity was restored in refractory lines upon introduction of SLC46A3, suggesting that expression of SLC46A3 may be more predictive of activity than target antigen levels alone. Interrogation of primary multiple myeloma samples indicated a range of SLC46A3 expression, including samples with undetectable levels like multiple myeloma cell lines resistant to BCMA-targeting DM1 and SG3376 ADCs.Conclusions:Our findings support SLC46A3 as a potential patient selection biomarker with immediate relevance to clinical trials involving these ADCs.
USP6 Confers Sensitivity to IFN-Mediated Apoptosis through Modulation of TRAIL Signaling in Ewing Sarcoma
Authors: Henrich Ian C. , Young Robert , Quick Laura , Oliveira Andre M. , Chou Margaret M. 
Published: August 2018

Abstract

Ewing sarcoma is the second most common sarcoma of the bone, afflicting predominantly the pediatric population. Although patients with localized disease exhibit favorable survival rates, patients with metastatic disease suffer a dismal 5-year rate of approximately 25%. Thus, there is a great need to develop treatments to combat the disseminated disease. Ubiquitin-specific protease 6 (USP6/TRE17) has been implicated as the key etiologic factor in several benign mesenchymal tumors, including nodular fasciitis and aneurysmal bone cyst (ABC). However, the role of USP6 in the biology of malignant entities remains unexplored. Previously, it was observed that USP6 is sufficient to drive formation of tumors mimicking ABC and nodular fasciitis, and that it functions through JAK1/STAT3 signaling. However, in the context of Ewing sarcoma, USP6 does not enhance the transformation, but rather triggers an IFN response signature, both in cultured Ewing sarcoma cells in vitro and in clinical specimens in vivo. Not only does USP6 independently induce activation of the IFN signaling mediators, JAK1 and STAT1, but it also renders Ewing sarcoma cells exquisitely responsive to exogenous IFNs, potentiating activation of STAT1 and STAT3. Furthermore, IFNβ (a type I IFN) induces apoptosis specifically in USP6-positive but not USP6-negative Ewing sarcoma cells. Finally, apoptosis is mediated through the proapoptotic ligand TRAIL, which is synergistically induced by type I IFN and USP6.

Implications:
These findings provide the first insights into USP6 functions in a clinically relevant malignant entity, and raise the possibility of using IFN for targeting USP6-positive Ewing sarcoma.
A2AR Antagonism with CPI-444 Induces Antitumor Responses and Augments Efficacy to Anti–PD-(L)1 and Anti–CTLA-4 in Preclinical Models
Authors: Willingham Stephen B. , Ho Po Y. , Hotson Andrew , Hill Craig , Piccione Emily C. , Hsieh Jessica , Liu Liang , Buggy Joseph J. , McCaffery Ian , Miller Richard A. 
Published: August 2018

AbstractAdenosine signaling through A2A receptors (A2AR) expressed on immune cells suppresses antitumor immunity. CPI-444 is a potent, selective, oral A2AR antagonist. Blockade of A2AR with CPI-444 restored T-cell signaling, IL2, and IFNγ production that were suppressed by adenosine analogues in vitro. CPI-444 treatment led to dose-dependent inhibition of tumor growth in multiple syngeneic mouse tumor models. Concentrations of extracellular adenosine in the tumor microenvironment, measured using microdialysis, were approximately 100–150 nmol/L and were higher than corresponding subcutaneous tissue. Combining CPI-444 with anti–PD-L1 or anti–CTLA-4 treatment eliminated tumors in up to 90% of treated mice, including restoration of immune responses in models that incompletely responded to anti–PD-L1 or anti–CTLA-4 monotherapy. Tumor growth was fully inhibited when mice with cleared tumors were later rechallenged, indicating that CPI-444 induced systemic antitumor immune memory. CD8+ T-cell depletion abrogated the efficacy of CPI-444 with and without anti–PD-L1 treatment, demonstrating a role for CD8+ T cells in mediating primary and secondary immune responses. The antitumor efficacy of CPI-444 with and without anti–PD-L1 was associated with increased T-cell activation, a compensatory increase in CD73 expression, and induction of a Th1 gene expression signature consistent with immune activation. These results suggest a broad role for adenosine-mediated immunosuppression in tumors and justify the further evaluation of CPI-444 as a therapeutic agent in patients with solid tumors. Cancer Immunol Res; 6(10); 1136–49. ©2018 AACR.