bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect ofSaccharomyces boulardiiin dogs with chronic enteropathies: double‐blinded, placebo‐controlled study
Authors: D'Angelo Simona , Fracassi Federico , Bresciani Francesca , Galuppi Roberta , Diana Alessia , Linta Nikolina , Bettini Giuliano , Morini Maria , Pietra Marco 
Published: December 2017

Saccharomyces boulardiiis used to treat acute and chronic enteropathies in humans, but to date, no studies have evaluated the use of this yeast in dogs. The current study, a prospective non‐randomised, double‐blinded, placebo‐controlled study, evaluated the effects ofS boulardiiin healthy dogs and dogs with chronic enteropathies (CE). Four healthy dogs and 20 dogs with CE were included. In healthy dogs,S boulardiiwas administered for 10 days. Possible short‐term adverse effects were recorded, and quantitative stool cultures for yeasts were performed. In dogs with CE,S boulardiior a placebo was administered in addition to standard treatment protocols. Canine Chronic Enteropathy Clinical Activity Index, abdominal ultrasonography, gastroenteroscopy and histology were performed at the time of diagnosis and after 60 days of treatment. In healthy dogs,S boulardiireached a steady state in five days and was completely eliminated on day 4 after administration. No short‐term side effects were seen. Clinical activity index, stool frequency, stool consistency and body condition score improved significantly in dogs with CE receivingS boulardiiversus the placebo. In conclusion,S boulardiican be safely used in dogs with CE and seems to achieve better control of clinical signs than standard therapy alone.
Geophysical observations and structural models of two shallow caves in gypsum/anhydrite-bearing rocks in Germany
Authors: Kaufmann Georg , Romanov Douchko 
Published: December 2017

Abstract
The development of subsurface voids and cavities in soluble rocks is controlled by the hydrological and chemical processes in the host rock. Water (enriched with carbon dioxide) percolates through fractures and bedding partings of the host rock and removes material from the rock surface. As this enlargement is a highly heterogeneous process, only some fractures and bedding partings become significantly enlarged, evolving towards larger voids and caves. The size of the enlarged voids, often reaching the metre scale, can result in mechanically unstable structures, which, when close to the surface, are prone to collapse and thus are a hazard to infrastructure. We explored two caves in the anhydrite host rock of the Permian Zechstein sequences in northern Germany using geophysical measurements: the Kalkberghöhle close to Bad Segeberg (Hamburg region) and the Jettenhöhle close to Osterode (Harz region). Based on the results of gravity and electrical measurements, we were able to identify the cave voids and to characterize the local geological setting. Using these indirect geophysical observations, we deduced a structural model for both cave sites by numerical modelling. Our structural models were successfully calibrated against the Bouguer gravity data.
Occipitocervical Hemolymphangioma in an Adult with Neck Pain and Stiffness: Case Report and Literature Review
Authors: Li Yongchao , Zhang Xing , Pang Xiaodong , Yang Liang , Peng Baogan 
Published: December 2017

Introduction. Hemolymphangioma is an extremely rare malformation of the lymphatic and blood vessels. A limited number of hemolymphangioma cases occurring in the pancreas, extremities, spleen, and other organs have been reported until September 2017. To the best of our knowledge, no cases of hemolymphangioma in the occipitocervical region have been reported in the literature. Case Presentation. We reported the case of a 23-year-old male patient with an occipitocervical lesion presenting atypically as neck pain and stiffness over a period of five months. Although hemolymphangioma has historically demonstrated a female predilection (2.25 : 1 female to male) and presentation in the third to fourth decades of life, this case is an atypical manifestation occurring in a young male patient. The clinical characteristics and management choices of this uncommon case of hemolymphangioma in the occipitocervical region are discussed, and a review based on the available literature is also presented. Conclusion. Hemolymphangioma of the occipitocervical region is an uncommon presentation of a rare lesion. Although rare, hemolymphangioma should be considered a differential diagnosis for masses occurring in the occipitocervical region. Complete surgical resection is the treatment of choice and affords a good prognosis.
Radiotherapy-Activated Cancer-Associated Fibroblasts Promote Tumor Progression through Paracrine IGF1R Activation
Authors: Tommelein Joke , De Vlieghere Elly , Verset Laurine , Melsens Elodie , Leenders Justine , Descamps Benedicte , Debucquoy Annelies , Vanhove Christian , Pauwels Patrick , Gespach Christian P. , Vral Anne , De Boeck Astrid , Haustermans Karin , de Tullio Pascal , Ceelen Wim , Demetter Pieter , Boterberg Tom , Bracke Marc , De Wever Olivier 
Published: December 2017

Abstract
Preoperative radiotherapy (RT) is a mainstay in the management of rectal cancer, a tumor characterized by desmoplastic stroma containing cancer-associated fibroblasts (CAF). Although CAFs are abundantly present, the effects of RT to CAF and its impact on cancer cells are unknown. We evaluated the damage responses of CAF to RT and investigated changes in colorectal cancer cell growth, transcriptome, metabolome, and kinome in response to paracrine signals emerging from irradiated CAF. RT to CAF induced DNA damage, p53 activation, cell-cycle arrest, and secretion of paracrine mediators, including insulin-like growth factor-1 (IGF1). Subsequently, RT-activated CAFs promoted survival of colorectal cancer cells, as well as a metabolic switch favoring glutamine consumption through IGF1 receptor (IGF1R) activation. RT followed by IGF1R neutralization in orthotopic colorectal cancer models reduced the number of mice with organ metastases. Activation of the downstream IGF1R mediator mTOR was significantly higher in matched (intrapatient) samples and in unmatched (interpatient) samples from rectal cancer patients after neoadjuvant chemoradiotherapy. Taken together, our data support the notion that paracrine IGF1/IGF1R signaling initiated by RT-activated CAF worsens colorectal cancer progression, establishing a preclinical rationale to target this activation loop to further improve clinical responses and patient survival.
Significance: These findings reveal that paracrine IGF1/IGF1R signaling promotes colorectal cancer progression, establishing a preclinical rationale to target this activation loop. Cancer Res; 78(3); 659–70. ©2017 AACR.
Improved Tumor Penetration and Single-Cell Targeting of Antibody–Drug Conjugates Increases Anticancer Efficacy and Host Survival
Authors: Cilliers Cornelius , Menezes Bruna , Nessler Ian , Linderman Jennifer , Thurber Greg M. 
Published: December 2017

Abstract
Current antibody–drug conjugates (ADC) have made advances in engineering the antibody, linker, conjugation site, small-molecule payload, and drug-to-antibody ratio (DAR). However, the relationship between heterogeneous intratumoral distribution and efficacy of ADCs is poorly understood. Here, we compared trastuzumab and ado-trastuzumab emtansine (T-DM1) to study the impact of ADC tumor distribution on efficacy. In a mouse xenograft model insensitive to trastuzumab, coadministration of trastuzumab with a fixed dose of T-DM1 at 3:1 and 8:1 ratios dramatically improved ADC tumor penetration and resulted in twice the improvement in median survival compared with T-DM1 alone. In this setting, the effective DAR was lowered, decreasing the amount of payload delivered to each targeted cell but increasing the number of cells that received payload. This result is counterintuitive because trastuzumab acts as an antagonist in vitro and has no single-agent efficacy in vivo, yet improves the effectiveness of T-DM1 in vivo. Novel dual-channel fluorescence ratios quantified single-cell ADC uptake and metabolism and confirmed that the in vivo cellular dose of T-DM1 alone exceeded the minimum required for efficacy in this model. In addition, this technique characterized cellular pharmacokinetics with heterogeneous delivery after 1 day, degradation and payload release by 2 days, and in vitro cell killing and in vivo tumor shrinkage 2 to 3 days later. This work demonstrates that the intratumoral distribution of ADC, independent of payload dose or plasma clearance, plays a major role in ADC efficacy.
Significance: This study shows how lowering the drug-to-antibody ratio during treatment can improve the intratumoral distribution of a antibody-drug conjugate, with implications for improving the efficacy of this class of cancer drugs. Cancer Res; 78(3); 758–68. ©2017 AACR.
Aptamer-Conjugated Extracellular Nanovesicles for Targeted Drug Delivery
Authors: Wan Yuan , Wang Lixue , Zhu Chuandong , Zheng Qin , Wang Guoxiang , Tong Jinlong , Fang Yuan , Xia Yiqiu , Cheng Gong , He Xia , Zheng Si-Yang 
Published: December 2017

Abstract
Extracellular nanovesicles (ENV) released by many cells contain lipids, proteins, and nucleic acids that contribute to intercellular communication. ENVs have emerged as biomarkers and therapeutic targets but they have also been explored as drug delivery vehicles. However, for the latter application, clinical translation has been limited by low yield and inadequate targeting effects. ENV vectors with desired targeting properties can be produced from parental cells engineered to express membrane-bound targeting ligands, or they can be generated by fusion with targeting liposomes; however, neither approach has met clinical requirements. In this study, we demonstrate that mechanical extrusion of approximately 107 cells grafted with lipidated ligands can generate cancer cell–targeting ENV and can be prepared in approximately 1 hour. This rapid and economic approach could pave the way for clinical implementation in the future.
Significance: A new and rapid method for production of drug-targeting nanovesicles has implications for cancer treatment by chimeric antigen receptor T cells and other therapies. Cancer Res; 78(3); 798–808. ©2017 AACR.
First-in-Human Phase I Study of Single-agent Vanucizumab, A First-in-Class Bispecific Anti-Angiopoietin-2/Anti-VEGF-A Antibody, in Adult Patients with Advanced Solid Tumors
Authors: Hidalgo Manuel , Martinez-Garcia Maria , Le Tourneau Christophe , Massard Christophe , Garralda Elena , Boni Valentina , Taus Alvaro , Albanell Joan , Sablin Marie-Paule , Alt Marie , Bahleda Ratislav , Varga Andrea , Boetsch Christophe , Franjkovic Izolda , Heil Florian , Lahr Angelika , Lechner Katharina , Morel Anthony , Nayak Tapan , Rossomanno Simona , Smart Kevin , Stubenrauch Kay , Krieter Oliver 
Published: December 2017

Abstract
Purpose: Vanucizumab is an investigational antiangiogenic, first-in-class, bispecific mAb targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies.
Experimental Design: Patients received escalating biweekly (3–30 mg/kg) or weekly (10–30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control.
Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg biweekly dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related grade ≥3 toxicities. Toxicity was generally higher with weekly than biweekly dosing. A MTD of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6–9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in KTRANS (measured by dynamic contrast-enhanced MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2,000 mg biweekly dose (phamacokinetically equivalent to 30 mg/kg biweekly) was recommended for further investigation.
Conclusions: Biweekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging antitumor activity in this heterogeneous population. Clin Cancer Res; 24(7); 1536–45. ©2017 AACR.
T Cells Expressing Checkpoint Receptor TIGIT Are Enriched in Follicular Lymphoma Tumors and Characterized by Reversible Suppression of T-cell Receptor Signaling
Authors: Josefsson Sarah E. , Huse Kanutte , Kolstad Arne , Beiske Klaus , Pende Daniela , Steen Chloé B. , Inderberg Else Marit , Lingjærde Ole Christian , Østenstad Bjørn , Smeland Erlend B. , Levy Ronald , Irish Jonathan M. , Myklebust June H. 
Published: December 2017

Abstract
Purpose: T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for immune checkpoint blockade is unknown. Characterizing coinhibitory receptor expression patterns and signaling responses in FL T-cell subsets might reveal new therapeutic targets.
Experimental Design: Surface expression of 9 coinhibitory receptors governing T-cell function was characterized in T-cell subsets from FL lymph node tumors and from healthy donor tonsils and peripheral blood samples, using high-dimensional flow cytometry. The results were integrated with T-cell receptor (TCR)-induced signaling and cytokine production. Expression of T-cell immunoglobulin and ITIM domain (TIGIT) ligands was detected by immunohistochemistry.
Results: TIGIT was a frequently expressed coinhibitory receptor in FL, expressed by the majority of CD8 T effector memory cells, which commonly coexpressed exhaustion markers such as PD-1 and CD244. CD8 FL T cells demonstrated highly reduced TCR-induced phosphorylation (p) of ERK and reduced production of IFNγ, while TCR proximal signaling (p-CD3ζ, p-SLP76) was not affected. The TIGIT ligands CD112 and CD155 were expressed by follicular dendritic cells in the tumor microenvironment. Dysfunctional TCR signaling correlated with TIGIT expression in FL CD8 T cells and could be fully restored upon in vitro culture. The costimulatory receptor CD226 was downregulated in TIGIT+ compared with TIGIT− CD8 FL T cells, further skewing the balance toward immunosuppression.
Conclusions: TIGIT blockade is a relevant strategy for improved immunotherapy in FL. A deeper understanding of the interplay between coinhibitory receptors and key T-cell signaling events can further assist in engineering immunotherapeutic regimens to improve clinical outcomes of cancer patients. Clin Cancer Res; 24(4); 870–81. ©2017 AACR.
Multidisciplinary Approach to Understand Medial Arterial Calcification
Authors: Gourgas Ophélie , Marulanda Juliana , Zhang Peng , Murshed Monzur , Cerruti Marta 
Published: December 2017

Objective—
Vascular calcification significantly increases morbidity in life-threatening diseases, and no treatments are available because of lack of understanding of the underlying molecular mechanism. Here, we study the physicochemical details of mineral nucleation and growth in an animal model that faithfully recapitulates medial arterial calcification in humans, to understand how pathological calcification is initiated on the vascular extracellular matrix.

Approach and Results—
MGP (matrix Gla protein) is a potent mineralization inhibitor. We study the evolution of medial calcification in MGP-deficient mice over the course of 5 weeks using a combination of material science techniques and find that mineral composition and crystallinity evolve over time and space. We show that calcium is adsorbed first and then amorphous calcium phosphate and octacalcium phosphate forms, which then transform into hydroxyapatite and carbonated apatite. These events are repeated after each nucleation event, providing a snapshot of the overall mineral evolution at each time point analyzed.

Conclusions—
Our results show that an interdisciplinary approach combining animal models and materials science can provide insights into the mechanism of vascular calcification and suggest the importance of analyzing mineral phases, rather than just overall mineralization extent, to diagnose and possibly prevent disease development.
Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy
Authors: Diguet Nicolas , Trammell Samuel A.J. , Tannous Cynthia , Deloux Robin , Piquereau Jérôme , Mougenot Nathalie , Gouge Anne , Gressette Mélanie , Manoury Boris , Blanc Jocelyne , Breton Marie , Decaux Jean-François , Lavery Gareth G. , Baczkó István , Zoll Joffrey , Garnier Anne , Li Zhenlin , Brenner Charles , Mericskay Mathias 
Published: December 2017

Background:

Myocardial metabolic impairment is a major feature in chronic heart failure. As the major coenzyme in fuel oxidation and oxidative phosphorylation and a substrate for enzymes signaling energy stress and oxidative stress response, nicotinamide adenine dinucleotide (NAD
+
) is emerging as a metabolic target in a number of diseases including heart failure. Little is known on the mechanisms regulating homeostasis of NAD
+
in the failing heart.

Methods:

To explore possible alterations of NAD
+
homeostasis in the failing heart, we quantified the expression of NAD
+
biosynthetic enzymes in the human failing heart and in the heart of a mouse model of dilated cardiomyopathy (DCM) triggered by Serum Response Factor transcription factor depletion in the heart (SRF
HKO
) or of cardiac hypertrophy triggered by transverse aorta constriction. We studied the impact of NAD
+
precursor supplementation on cardiac function in both mouse models.

Results:

We observed a 30% loss in levels of NAD
+
in the murine failing heart of both DCM and transverse aorta constriction mice that was accompanied by a decrease in expression of the nicotinamide phosphoribosyltransferase enzyme that recycles the nicotinamide precursor, whereas the nicotinamide riboside kinase 2 (NMRK2) that phosphorylates the nicotinamide riboside precursor is increased, to a higher level in the DCM (40-fold) than in transverse aorta constriction (4-fold). This shift was also observed in human failing heart biopsies in comparison with nonfailing controls. We show that the
Nmrk2
gene is an AMP-activated protein kinase and peroxisome proliferator-activated receptor α responsive gene that is activated by energy stress and NAD
+
depletion in isolated rat cardiomyocytes. Nicotinamide riboside efficiently rescues NAD
+
synthesis in response to FK866-mediated inhibition of nicotinamide phosphoribosyltransferase and stimulates glycolysis in cardiomyocytes. Accordingly, we show that nicotinamide riboside supplementation in food attenuates the development of heart failure in mice, more robustly in DCM, and partially after transverse aorta constriction, by stabilizing myocardial NAD
+
levels in the failing heart. Nicotinamide riboside treatment also robustly increases the myocardial levels of 3 metabolites, nicotinic acid adenine dinucleotide, methylnicotinamide, and N1-methyl-4-pyridone-5-carboxamide, that can be used as validation biomarkers for the treatment.

Conclusions:
The data show that nicotinamide riboside, the most energy-efficient among NAD precursors, could be useful for treatment of heart failure, notably in the context of DCM, a disease with few therapeutic options.
Relation Between Blood Pressure and Clinical Outcome in Hypertensive Subjects With Previous Stroke
Authors: Lee Chan Joo , Hwang Jinseub , Oh Jaewon , Lee Sang‐Hak , Kang Seok‐Min , Kim Hyeon Chang , Park Sungha 
Published: December 2017

Background
This study investigated whether a mean blood pressure (BP) of <130/80 mm Hg is associated with further reduction in cardiovascular outcomes in treated hypertensive subjects with previous stroke.

Methods and Results

Subjects from the Korea National Health Insurance Service health examinee cohort diagnosed as having stroke and hypertension from January 1st, 2003 and December 31st, 2006 (N=2320) were grouped according to mean systolic (<130, 130–<140, and ≥140 mm Hg) and diastolic (<80, 80–<90, and ≥90 mm Hg) BP recorded during follow‐up health examinations. All‐cause and cardiovascular mortality over 11 years were compared. Compared with subjects with a systolic BP of ≥140 mm Hg (N=736), subjects with a systolic BP of 130 to <140 mm Hg (N=793) had a significantly lower risk of all‐cause death (hazard ratio [
HR
], 0.61; 95% confidence interval [CI], 0.47–0.79;
P
<0.001), cardiovascular mortality (
HR
, 0.39; 95%
CI
, 0.25–0.61;
P
<0.001), and fatal ischemic stroke (
HR
, 0.25; 95%
CI
, 0.10–0.63;
P
=0.003). Systolic BP of <130 mm Hg (N=791) was associated with lower risk of nonfatal hemorrhagic stroke. Subjects with a diastolic BP of 80 to <90 mm Hg (N=1100) had significantly lower risk of all‐cause death (
HR
, 0.60, 95%
CI
, 0.45–0.80;
P
<0.001) and cardiovascular mortality (
HR
, 0.45; 95%
CI
, 0.30–0.70;
P
<0.001) than those with a diastolic BP of ≥90 mm Hg (N=342). Diastolic BP of <80 mm Hg (N=878) was associated with reduced risk of nonfatal hemorrhagic stroke and further lowering of all‐cause mortality and cardiovascular mortality.

Conclusions
BP of <130/80 mm Hg was associated with improved outcomes in hypertensive subjects with previous stroke.
The African Court on Human and Peoples’ Rights and Its Protection of the Right to a Fair Trial
Authors: Mujuzi Jamil Ddamulira 
Published: December 2017

Abstract
Article 3(1) of the Protocol to the African Charter on Human and Peoples’ Rights on the Establishment of an African Court on Human and Peoples’ Rights provides that: “[t]he jurisdiction of the Court shall extend to all cases and disputes submitted to it concerning the interpretation and application of the [African] Charter, this Protocol and any other relevant Human Rights instrument ratified by the States concerned.” Since its establishment, the African Court on Human and Peoples’ Rights has handed down judgments dealing, inter alia, with the right to a fair trial under Article 7 of the African Charter on Human and Peoples’ Rights. This article discusses these judgments to highlight how the Court has interpreted or applied Article 7 of the African Charter. The author will analyse the jurisprudence of the Court on the right to a fair trial and in particular discuss the following themes that have emerged from this jurisprudence: the Court’s interpretation of the components of the right to a fair trial; the right to be heard and the right to defend oneself; the right to legal assistance, including legal aid; manifest errors in the trial; the right to be tried within a reasonable time; and the role of a prosecutor in contributing to the fairness of the trial. The author also discusses how the African Court has invoked other treaties to interpret the relevant provisions of the African Charter and how the African Court has interpreted other treaties apart from the African Charter.