bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contrast‐enhanced ultrasonography features of hepatobiliary neoplasms in cats
Authors: Banzato Tommaso , Burti Silvia , Rubini Giuseppe , Orlandi Riccardo , Bargellini Paolo , Bonsembiante Federico , Zotti Alessandro 
Published: October 2019

BackgroundContrast‐enhanced ultrasonography (CEUS) features of primary hepatobiliary neoplasms have been reported in dogs but no information is available in cats.MethodsQualitative and quantitative features of bile duct adenomas (BDAs, n=20), bile duct carcinomas (BDCs, n=16), and hepatocellular carcinomas (HCCs, n=8) are described in 44 cats.ResultsThere was an overlap in CEUS qualitative features between different histotypes, both in wash‐in and wash‐out phases. Distinction between different neoplasms based only on the CEUS qualitative features was not possible. At peak of enhancement, the BDAs, BDCs and HCCs showed a large range of echogenicities, from hypoenhancement to hyperenhancement, in comparison to the liver parenchyma. Eight of 20 BDAs showed inhomogeneous hyperenhancement during wash‐in, which is a feature reported as typical of malignant lesions in dogs. BDC had a significantly faster wash‐in compared with both BDA and HCC but the diagnostic accuracy of all the included quantitative variables was only moderate. No significant differences in the wash‐out quantitative features of BDA and BDC were evident.ConclusionThere is poor evidence that CEUS may be used to distinguish between different primary hepatobiliary neoplasms in cats.
DHA supplementation decreases resting metabolic rate in healthy young females
Authors: Jannas-Vela Sebastian , Klingel Shannon L. , Mutch David M. , Spriet Lawrence L. 
Published: October 2019

This study examined the independent effects of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acid supplementation on resting metabolic rate (RMR) and substrate oxidation in young healthy females and males. EPA or DHA supplementation had no effect on RMR and substrate oxidation in males, while DHA reduced RMR by ∼7% (p < 0.01) in females. In conclusion, these data establish potential sex differences on RMR in response to DHA supplements. Novelty Supplementing with DHA decreases resting energy expenditure in healthy young females but not males.
B-meson production in the general-mass variable-flavour-number scheme and LHC data
Authors: Benzke M. , Kniehl B. A. , Kramer G. , Schienbein I. , Spiesberger H. 
Published: October 2019

Abstract
We study inclusive B-meson production in pp collisions at the LHC and compare experimental data with predictions of the general-mass variable-flavour-number scheme at next-to-leading order of perturbative QCD. We find almost perfect agreement provided that the factorization scale parameters and the parton distribution functions are chosen appropriately.
Case Studies in Physiology: Visualization of blood recirculation in a femoral artery “trifurcation” using ultrasound vector flow imaging
Authors: Au Jason S. , Yiu Billy Y. S. , Yu Alfred C. H. 
Published: October 2019

The femoral bifurcation is typically composed of a common femoral artery that bifurcates into the superficial (SFA) and deep (DFA) femoral arteries, with the lateral circumflex femoral artery (LCFA) branching distal to the origin of the DFA. We report a unique case of a 22-yr-old woman with a femoral “trifurcation,” where the origin of the LCFA coincides with the origin of the DFA, resulting in a true three-way branching of the common femoral artery. We characterized the complex hemodynamics of the trifurcation region with ultrasound vector flow imaging at rest, and during 80 mmHg cuff compression of the calf to induce greater oscillatory blood flow. At rest, a clear trifurcation is observed with color Doppler imaging, while vector flow imaging further revealed a large area of flow circulation proximal to the LCFA and DFA. Cuff compression reduced SFA blood flow to 0 cm3/min, characterized by almost constant retrograde blood flow throughout diastole. When visualized with vector flow imaging, diastolic retrograde blood flow from the SFA appeared to reperfuse the DFA and LCFA during late systole, eliminating the retrograde flow component and providing a secondary source of anterograde blood flow to the thigh. In a rare case of a femoral trifurcation, we demonstrate blood recirculation patterns at rest, as well as collateral retrograde blood flow redistribution during lower limb compression. While it is unknown whether these trifurcation findings extend to typical bifurcations, it is evident that advanced methods of blood flow characterization are necessary to visualize and study complex vascular regions. NEW & NOTEWORTHY A femoral “trifurcation” is observed when the lateral circumflex femoral artery has an atypical proximal origin, branching at the same level as the superficial and deep femoral arteries. Ultrasound vector flow imaging at 750 fps was able to reveal substantial blood recirculation within the trifurcation at rest, as well as unique redistribution of blood flow between downstream branches during external cuff manipulation of retrograde flow, indicating novel ways in which diastolic blood flow is controlled.
Establishing the V̇o2 versus constant-work-rate relationship from ramp-incremental exercise: simple strategies for an unsolved problem
Authors: Iannetta Danilo , de Almeida Azevedo Rafael , Keir Daniel A. , Murias Juan M. 
Published: October 2019

The dissociation between constant work rate of O2 uptake (V̇o2) and ramp V̇o2 at a given work rate might be mitigated during slowly increasing ramp protocols. This study characterized the V̇o2 dynamics in response to five different ramp protocols and constant-work-rate trials at the maximal metabolic steady state (MMSS) to characterize 1) the V̇o2 gain (G) in the moderate, heavy, and severe domains, 2) the mean response time of V̇o2 (MRT), and 3) the work rates at lactate threshold (LT) and respiratory compensation point (RCP). Eleven young individuals performed five ramp tests (5, 10, 15, 25, and 30 W/min), four to five time-to-exhaustions for critical power estimation, and two to three constant-work-rate trials for confirmation of the work rate at MMSS. G was greatest during the slowest ramp and progressively decreased with increasing ramp slopes (from ~12 to ~8 ml·min−1·W−1, P < 0.05). The MRT was smallest during the slowest ramp slopes and progressively increased with faster ramp slopes (1 ± 1, 2 ± 1, 5 ± 3, and 10 ± 4, 15 ± 6 W, P < 0.05). After “left shifting” the ramp V̇o2 by the MRT, the work rate at LT was constant regardless of the ramp slope (~150 W, P > 0.05). The work rate at MMSS was 215 ± 55 W and was similar and highly correlated with the work rate at RCP during the 5 W/min ramp ( P > 0.05, r = 0.99; Lin’s concordance coefficient = 0.99; bias = −3 W; root mean square error = 6 W). Findings showed that the dynamics of V̇o2 (i.e., G) during ramp exercise explain the apparent dichotomy existing with constant-work-rate exercise. When these dynamics are appropriately “resolved”, LT is constant regardless of the ramp slope of choice, and RCP and MMSS display minimal variations between each other. NEW & NOTEWORTHY This study demonstrates that the dynamics of V̇o2 during ramp-incremental exercise are dependent on the characteristics of the increments in work rate, such that during slow-incrementing ramp protocols the magnitude of the dissociation between ramp V̇o2 and constant V̇o2 at a given work rate is reduced. Accurately accounting for these dynamics ensures correct characterizations of the V̇o2 kinetics at ramp onset and allows appropriate comparisons between ramp and constant-work-rate exercise-derived indexes of exercise intensity.
MFF Regulation of Mitochondrial Cell Death Is a Therapeutic Target in Cancer
Authors: Seo Jae Ho , Chae Young Chan , Kossenkov Andrew V. , Lee Yu Geon , Tang Hsin-Yao , Agarwal Ekta , Gabrilovich Dmitry I. , Languino Lucia R. , Speicher David W. , Shastrula Prashanth K. , Storaci Alessandra Maria , Ferrero Stefano , Gaudioso Gabriella , Caroli Manuela , Tosi Davide , Giroda Massimo , Vaira Valentina , Rebecca Vito W. , Herlyn Meenhard , Xiao Min , Fingerman Dylan , Martorella Alessandra , Skordalakes Emmanuel , Altieri Dario C. 
Published: October 2019

Abstract

The regulators of mitochondrial cell death in cancer have remained elusive, hampering the development of new therapies. Here, we showed that protein isoforms of mitochondrial fission factor (MFF1 and MFF2), a molecule that controls mitochondrial size and shape, that is, mitochondrial dynamics, were overexpressed in patients with non–small cell lung cancer and formed homo- and heterodimeric complexes with the voltage-dependent anion channel-1 (VDAC1), a key regulator of mitochondrial outer membrane permeability. MFF inserted into the interior hole of the VDAC1 ring using Arg225, Arg236, and Gln241 as key contact sites. A cell-permeable MFF Ser223-Leu243 d-enantiomeric peptidomimetic disrupted the MFF–VDAC1 complex, acutely depolarized mitochondria, and triggered cell death in heterogeneous tumor types, including drug-resistant melanoma, but had no effect on normal cells. In preclinical models, treatment with the MFF peptidomimetic was well-tolerated and demonstrated anticancer activity in patient-derived xenografts, primary breast and lung adenocarcinoma 3D organoids, and glioblastoma neurospheres. These data identify the MFF–VDAC1 complex as a novel regulator of mitochondrial cell death and an actionable therapeutic target in cancer.

Significance:
These findings describe mitochondrial fission regulation using a peptidomimetic agent that disturbs the MFF–VDAC complex and displays anticancer activity in multiple tumor models.
See related commentary by Rao, p. 6074
HER2-Overexpressing/Amplified Breast Cancer as a Testing Ground for Antibody–Drug Conjugate Drug Development in Solid Tumors
Authors: Pegram Mark D. , Miles David , Tsui C. Kimberly , Zong Yu 
Published: October 2019

Abstract
Efficacy data from the KATHERINE clinical trial, comparing the HER2-directed antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) to trastuzumab in patients with early-stage HER2-amplified/overexpressing breast cancer with residual disease after neoadjuvant therapy, demonstrates superiority of T-DM1 (HR for invasive disease or death, 0.50; P &lt; 0.001). This establishes foundational precedent for ADCs as effective therapy for treatment of subclinical micrometastasis in an adjuvant (or post-neoadjuvant) early-stage solid tumor setting. Despite this achievement, general principles from proposed systems pharmacokinetic modeling for intracellular processing of ADCs indicate potential shortcomings of T-DM1: (i) Cmax limited by toxicities; (ii) slow internalization rate; (iii) resistance mechanisms due to defects in intracellular trafficking [loss of lysosomal transporter solute carrier family 46 member 3, (SLC46A3)], and increased expression of drug transporters MDR1 and MRP1; and (iv) lack of payload bystander effects limiting utility in tumors with heterogeneous HER2 expression. These handicaps may explain the inferiority of T-DM1–based therapy in the neoadjuvant and first-line metastatic HER2+ breast cancer settings, and lack of superiority to chemotherapy in HER2+ advanced gastric cancer. In this review, we discuss how each of these limitations is being addressed by manipulating internalization and trafficking using HER2:HER2 bispecific or biparatopic antibody backbones, using site-specific, fixed DAR conjugation chemistry, and payload swapping to exploit alternative intracellular targets and to promote bystander effects. Newer HER2-directed ADCs have impressive clinical activity even against tumors with lower levels of HER2 receptor expression. Finally, we highlight ongoing clinical efforts to combine HER2 ADCs with other treatment modalities, including chemotherapy, molecularly targeted therapies, and immunotherapy.
The Outcome of TGFβ Antagonism in Metastatic Breast Cancer Models In Vivo Reflects a Complex Balance between Tumor-Suppressive and Proprogression Activities of TGFβ
Authors: Yang Yuan , Yang Howard H. , Tang Binwu , Wu Alex Man Lai , Flanders Kathleen C. , Moshkovich Nellie , Weinberg Douglas S. , Welsh Michael A. , Weng Jia , Ochoa Humberto J. , Hu Tiffany Y. , Herrmann Michelle A. , Chen Jinqiu , Edmondson Elijah F. , Simpson R. Mark , Liu Fang , Liu Huaitian , Lee Maxwell P. , Wakefield Lalage M. 
Published: October 2019

Abstract

Purpose:
TGFβs are overexpressed in many advanced cancers and promote cancer progression through mechanisms that include suppression of immunosurveillance. Multiple strategies to antagonize the TGFβ pathway are in early-phase oncology trials. However, TGFβs also have tumor-suppressive activities early in tumorigenesis, and the extent to which these might be retained in advanced disease has not been fully explored.

Experimental Design:
A panel of 12 immunocompetent mouse allograft models of metastatic breast cancer was tested for the effect of neutralizing anti-TGFβ antibodies on lung metastatic burden. Extensive correlative biology analyses were performed to assess potential predictive biomarkers and probe underlying mechanisms.

Results:
Heterogeneous responses to anti-TGFβ treatment were observed, with 5 of 12 models (42%) showing suppression of metastasis, 4 of 12 (33%) showing no response, and 3 of 12 (25%) showing an undesirable stimulation (up to 9-fold) of metastasis. Inhibition of metastasis was immune-dependent, whereas stimulation of metastasis was immune-independent and targeted the tumor cell compartment, potentially affecting the cancer stem cell. Thus, the integrated outcome of TGFβ antagonism depends on a complex balance between enhancing effective antitumor immunity and disrupting persistent tumor-suppressive effects of TGFβ on the tumor cell. Applying transcriptomic signatures derived from treatment-naïve mouse primary tumors to human breast cancer datasets suggested that patients with breast cancer with high-grade, estrogen receptor–negative disease are most likely to benefit from anti-TGFβ therapy.

Conclusions:
Contrary to dogma, tumor-suppressive responses to TGFβ are retained in some advanced metastatic tumors. Safe deployment of TGFβ antagonists in the clinic will require good predictive biomarkers.
ctDNA in Gastric and Gastroesophageal Cancer: Prognostic, Predictive, or Preliminary?
Authors: Frankell Alexander M. , Smyth Elizabeth C. 
Published: October 2019

Abstract
In gastric and gastroesophageal adenocarcinoma, circulating tumor DNA identifies molecular drivers missed using routine tumor biopsy, can refine patient selection for targeted therapy, and may be prognostic following surgical resection. However, lack of standardization could impede adoption of this technology as a clinically useful tool; prospective validation in clinical trials is required.
See related article by Maron et al., p. 7098
Dual Inhibition of Angiopoietin-TIE2 and MET Alters the Tumor Microenvironment and Prolongs Survival in a Metastatic Model of Renal Cell Carcinoma
Authors: Elbanna May , Orillion Ashley R. , Damayanti Nur P. , Adelaiye-Ogala Remi , Shen Li , Miles Kiersten Marie , Chintala Sreenivasulu , Ciamporcero Eric , Ramakrishnan Swathi , Ku Sheng-yu , Rex Karen , Caenepeel Sean , Coxon Angela , Pili Roberto 
Published: October 2019

AbstractReceptor tyrosine kinase inhibitors have shown clinical benefit in clear cell renal cell carcinoma (ccRCC), but novel therapeutic strategies are needed. The angiopoietin/Tie2 and MET pathways have been implicated in tumor angiogenesis, metastases, and macrophage infiltration. In our study, we used trebananib, an angiopoietin 1/2 inhibitor, and a novel small-molecule MET kinase inhibitor in patient-derived xenograft (PDX) models of ccRCC. Our goal was to assess the ability of these compounds to alter the status of tumor-infiltrating macrophages, inhibit tumor growth and metastases, and prolong survival. Seven-week-old SCID mice were implanted subcutaneously or orthotopically with human ccRCC models. One month postimplantation, mice were treated with angiopoietin 1/2 inhibitor trebananib (AMG 386), MET kinase inhibitor, or combination. In our metastatic ccRCC PDX model, RP-R-02LM, trebananib alone, and in combination with a MET kinase inhibitor, significantly reduced lung metastases and M2 macrophage infiltration (P = 0.0075 and P = 0.0205, respectively). Survival studies revealed that treatment of the orthotopically implanted RP-R-02LM tumors yielded a significant increase in survival in both trebananib and combination groups. In addition, resection of the subcutaneously implanted primary tumor allowed for a significant survival advantage to the combination group compared with vehicle and both single-agent groups. Our results show that the combination of trebananib with a MET kinase inhibitor significantly inhibits the spread of metastases, reduces infiltrating M2-type macrophages, and prolongs survival in our highly metastatic ccRCC PDX model, suggesting a potential use for this combination therapy in treating patients with ccRCC.
A Multifunctional Therapy Approach for Cancer: Targeting Raf1- Mediated Inhibition of Cell Motility, Growth, and Interaction with the Microenvironment
Authors: Zhang Limin , Pattanayak Abhinandan , Li Wenqi , Ko Hyun-Kyung , Fowler Graham , Gordon Ryan , Bergan Raymond 
Published: October 2019

Abstract
Prostate cancer cells move from their primary site of origin, interact with a distant microenvironment, grow, and thereby cause death. It had heretofore not been possible to selectively inhibit cancer cell motility. Our group has recently shown that inhibition of intracellular activation of Raf1 with the small-molecule therapeutic KBU2046 permits, for the first time, selective inhibition of cell motility. We hypothesized that simultaneous disruption of multiple distinct functions that drive progression of prostate cancer to induce death would result in advanced disease control. Using a murine orthotopic implantation model of human prostate cancer metastasis, we demonstrate that combined treatment with KBU2046 and docetaxel retains docetaxel's antitumor action, but provides improved inhibition of metastasis, compared with monotherapy. KBU2046 does not interfere with hormone therapy, inclusive of enzalutamide-mediated inhibition of androgen receptor (AR) function and cell growth inhibition, and inclusive of the ability of castration to inhibit LNCaP-AR cell outgrowth in mice. Cell movement is necessary for osteoclast-mediated bone degradation. KBU2046 inhibits Raf1 and its downstream activation of MEK1/2 and ERK1/2 in osteoclasts, inhibiting cytoskeleton rearrangement, resorptive cavity formation, and bone destruction in vitro, with improved effects observed when the bone microenvironment is chemically modified by pretreatment with zoledronic acid. Using a murine cardiac injection model of human prostate cancer bone destruction quantified by CT, KBU2046 plus zoledronic exhibit improved inhibitory efficacy, compared with monotherapy. The combined disruption of pathways that drive cell movement, interaction with bone, and growth constitutes a multifunctional targeting strategy that provides advanced disease control.
ID1 Mediates Escape from TGFβ Tumor Suppression in Pancreatic Cancer
Authors: Huang Yun-Han , Hu Jing , Chen Fei , Lecomte Nicolas , Basnet Harihar , David Charles J. , Witkin Matthew D. , Allen Peter J. , Leach Steven D. , Hollmann Travis J. , Iacobuzio-Donahue Christine A. , Massagué Joan 
Published: October 2019

Abstract

TGFβ is an important tumor suppressor in pancreatic ductal adenocarcinoma (PDA), yet inactivation of TGFβ pathway components occurs in only half of PDA cases. TGFβ cooperates with oncogenic RAS signaling to trigger epithelial-to-mesenchymal transition (EMT) in premalignant pancreatic epithelial progenitors, which is coupled to apoptosis owing to an imbalance of SOX4 and KLF5 transcription factors. We report that PDAs that develop with the TGFβ pathway intact avert this apoptotic effect via ID1. ID1 family members are expressed in PDA progenitor cells and encode components of a set of core transcriptional regulators shared by PDAs. PDA progression selects against TGFβ-mediated repression of ID1. The sustained expression of ID1 uncouples EMT from apoptosis in PDA progenitors. AKT signaling and mechanisms linked to low-frequency genetic events converge on ID1 to preserve its expression in PDA. Our results identify ID1 as a crucial node and potential therapeutic target in PDA.

Significance:
Half of PDAs escape TGFβ-induced tumor suppression without inactivating the TGFβ pathway. We report that ID1 expression is selected for in PDAs and that ID1 uncouples TGFβ-induced EMT from apoptosis. ID1 thus emerges as a crucial regulatory node and a target of interest in PDA.
This article is highlighted in the In This Issue feature, p. 1
Mangue Bangue, filme-limite
Authors: Duarte Theo Costa 
Published: October 2019

O propósito deste artigo é apresentar uma análise do “filme-limite” Mangue Bangue (1971), de Neville d’Almeida, tendo-se em vista a sua proximidade a questões e propostas contemporâneas do parceiro do cineasta, o artista plástico Hélio Oiticica, e ressaltando a convergência de ambos os artistas na experimentação com a forma cinema em interface com distintas mídias visuais e audiovisuais. Releva-se o contexto de parcerias artísticas que persistiam clandestinamente em torno da experimentação formal, de busca de ampliação das sensibilidades, catalisada pela precariedade dos meios técnicos à disposição, por necessidade e negação às convenções do cinema narrativo-representativo-industrial e à repressão estatal no período mais duro da ditadura civil-militar brasileira.
Lipoprotein(a)-Lowering by 50 mg/dL (105 nmol/L) May Be Needed to Reduce Cardiovascular Disease 20% in Secondary Prevention
Authors: Madsen Christian M. , Kamstrup Pia R. , Langsted Anne , Varbo Anette , Nordestgaard Børge G. 
Published: October 2019

Objective:
High Lp(a) (lipoprotein[a]) cause cardiovascular disease (CVD) in a primary prevention setting; however, it is debated whether high Lp(a) lead to recurrent CVD events. We tested the latter hypothesis and estimated the Lp(a)-lowering needed for 5 years to reduce CVD events in a secondary prevention setting.

Approach and Results:
From the CGPS (Copenhagen General Population Study; 2003–2015) of 58 527 individuals with measurements of Lp(a), 2527 aged 20 to 79 with a history of CVD were studied. The primary end point was major adverse cardiovascular event (MACE). We also studied 1115 individuals with CVD from the CCHS (Copenhagen City Heart Study; 1991–1994) and the CIHDS (Copenhagen Ischemic Heart Disease Study; 1991–1993). During a median follow-up of 5 years (range, 0–13), 493 individuals (20%) experienced a MACE in the CGPS. MACE incidence rates per 1000 person-years were 29 (95% CI, 25–34) for individuals with Lp(a)<10 mg/dL, 35 (30–41) for 10 to 49 mg/dL, 42 (34–51) for 50 to 99 mg/dL, and 54 (42–70) for ≥100 mg/dL. Compared with individuals with Lp(a)<10 mg/dL (18 nmol/L), the multifactorially adjusted MACE incidence rate ratios were 1.28 (95% CI, 1.03–1.58) for 10 to 49 mg/dL (18–104 nmol/L), 1.44 (1.12–1.85) for 50 to 99 mg/dL (105–213 nmol/L), and 2.14 (1.57–2.92) for ≥100 mg/dL (214 nmol/L). Independent confirmation was obtained in individuals from the CCHS and CIHDS. To achieve 20% and 40% MACE risk reduction in secondary prevention, we estimated that plasma Lp(a) should be lowered by 50 mg/dL (95% CI, 27–138; 105 nmol/L [55–297]) and 99 mg/dL (95% CI, 54–273; 212 nmol/L [114–592]) for 5 years.

Conclusions:
High concentrations of Lp(a) are associated with high risk of recurrent CVD in individuals from the general population. This study suggests that Lp(a)-lowering by 50 mg/dL (105 nmol/L) short-term (ie, 5 years) may reduce CVD by 20% in a secondary prevention setting.