bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Pharmacology Considerations for the Development of Immune Checkpoint Inhibitors
Authors: Sheng Jennifer , Srivastava Shivani , Sanghavi Kinjal , Lu Zheng , Schmidt Brian J. , Bello Akintunde , Gupta Manish 
Published: September 2017

AbstractImmuno‐oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular‐targeted therapies. The most notable feature of immuno‐oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno‐oncology therapies. This review outlines the clinical pharmacology characteristics and development challenges for the 6 approved immunomodulatory monoclonal antibodies that target 2 immune checkpoint pathways: ipilimumab (an anti–cytotoxic T‐lymphocyte antigen‐4 antibody) and, more recently, nivolumab and pembrolizumab (both anti–programmed death‐1 antibodies) and atezolizumab, avelumab, and durvalumab (all anti–programmed death ligand‐1 antibodies). These agents have revealed much about the clinical pharmacology features of immune checkpoint inhibitors as a class, as well as the pharmacometric approaches used to support their clinical development and regulatory approval. The development experiences with these pioneering immuno‐oncology agents are likely to serve as useful guides in the discovery, progression, and approval of future drugs or combination of drugs in this class. This review includes summaries of the pharmacokinetics and exposure–response of the immune checkpoint inhibitors approved to date, as well as an overview of some quantitative systems pharmacology approaches. The ability of immuno‐oncology to meet its full potential will depend on overcoming development challenges, including the need for clear strategies to determine optimal dose and scheduling for monotherapy as well as combination approaches.
Characterization of lacquer films from the middle and late Chinese warring states period 476–221BC
Authors: Jin P.J. , Hu Y.L. , Ke Z.B. 
Published: September 2017

AbstractThe famous lacquer wares excavated from the Jiuliandun Tombs of the middle and late Warring States period (476–221 BC) were analyzed using scanning electron microscopy/energy as well as dispersive X‐ray spectrometry (SEM/EDS), Raman spectroscopy (RS), optical microscopy (OM), and X‐ray diffraction (XRD). The results showed a multilayer structure in the lacquer film, including a Qihui layer (a layer made of lacquer and various plasters), undercoat layer (or finishing coat) and colored paint layer mixed with various inorganic particles, such as quartz (SiO2) and hydroxyapatite [Ca5(PO4)3(OH)], as fillers in the Qihui layers or orpiment (As2S3) and cinnabar (HgS), which were used as a yellow or red pigment, respectively. With the help of elemental mapping images, a double‐layer structure of the lacquer plaster was observed, corresponding to a mixture of lacquer liquid and bone ash [Ca5(PO4)3(OH)], with large‐diameter particles in the ground lacquer layer near the wooden body and small quartz (SiO2) particles in upper lacquer layer. Specifically, quartz particles detected in the undercoat layer as fillers could be beneficial for improving the moshardness value, cost reduction and abrasive resistance of the lacquer film. In fact, the mixed method that used urushi and inorganic particles to form lacquer plaster was an important technological innovation and deeply influenced lacquering technologies worldwide. The results of this study will not only contribute to understanding the importance of lacquer skills in the Chinese Warring States but also provide information for cultural relic conservation as well as modern lacquer manufacturing for their protection and duplication.
Positive relationship between infliximab and adalimumab trough levels at completion of induction therapy with clinical response rates, at a tertiary referral center
Authors: Tighe Donal , Smith Sinead , O'Connor Anthony , Breslin Niall , Ryan Barbara , McNamara Deirdre 
Published: September 2017

Background and AimAnti‐tumor necrosis factor alpha (TNFα) therapies have improved outcomes for patients with inflammatory bowel disease. The aim of this study was to explore the relationship between infliximab (IFX) and adalimumab (ADL) trough and antibody levels with clinical response rates at the end of induction.MethodsThis was a prospective, single‐center study. Patients were recruited from July 2015 to August 2016. Inclusion criteria were all inflammatory bowel disease patients older than 17 years who started treatment with IFX or ADL. Baseline clinical disease activity indexes were performed. Clinical response was defined as HBI ≤3 or partial Mayo score ≤4% or <30% reduction from baseline. Anti‐TNFα trough and antibody levels were measured using standard ELISA techniques.ResultsThirty‐five patients were recruited, of whom 23 had Crohn's disease and 12 had ulcerative colitis. Eighteen were treated with ADL and 17 with IFX. The mean age of the cohort was 40.3 years, 62.9% were females, 34.3% were on concomitant thiopurines, and 25.7% had prior anti‐TNFα exposure. Overall response rate was 51.4%, 33.3% for ADL and 70.6% for IFX.Mean trough levels were 12.5 μg/mL for IFX and 4.4 μg/mL for ADL. There was a clear link between higher anti‐TNFα trough levels at the end of induction with clinical response rates. For IFX, mean trough level was 16.4 μg/mL for responders versus 5.3 μg/mL for non‐responders (P = 0.026). Area under the curve for association of IFX level at induction with clinical response was 0.864 (P = 0.0001). Similar link was present between higher ADL levels with clinical response, although not statistically significant.ConclusionHigher trough levels at the end of induction are associated with improved response. Ongoing work will define optimal targets at this key timeframe.
Comparing swallowing of capsule to endoscopic placement of capsule endoscopy in children
Authors: Burgess Christopher J , McIntyre Emma C , Withers Geoffrey D , Ee Looi C 
Published: September 2017

Background and AimCapsule endoscopy (CE) offers a method of directly visualizing areas of the small bowel not accessible by conventional endoscopy. Some children are unable to swallow the capsule requiring endoscopic placement under general anesthesia. The aim of the present study was to identify any differences between children requiring endoscopic placement and those able to swallow the capsule.MethodsRetrospective chart review of consecutive CE in a tertiary pediatric center was conducted. Patient demographics, outcomes, and complications between the two groups were noted. Paired t‐test comparing continuous variables and Fisher exact test for categorical data were used.ResultsA total of 104 CEs were performed in 88 patients, median age 12.8 (range: 1.6–18.5) years. Almost half, 49% (51/104), swallowed the capsule. Children requiring endoscopic placement were significantly younger (9.8 vs 14.2 years; P < 0.001), lighter (34.5 vs 54.9 kg; P < 0.0001), and had longer small intestinal transit time (308 vs 229 min; P < 0.0001). Positive findings were more likely in those who swallowed the capsule (50% vs 30%, P = 0.017), likely a reflection of the indications for procedure. Poor views were found in 30% (16/53) of patients in the endoscopic placement group due to iatrogenic bleeding from biopsies taken from concurrent procedures but did not affect outcome or subsequent patient management.ConclusionsCE is safe and well tolerated in children. Children requiring endoscopic placement were significantly younger, lighter, had longer small intestine transit time, and less likely to have positive findings. Concurrent biopsies during capsule placement increase the likelihood of inadequate views but did not affect outcome or management.
Pulmonary function in patients with ulcerative colitis and its relationship with disease severity
Authors: Goyal Ajesh , Ghoshal Uday C , Nath Alok , Jindal Shikha , Mohindra Samir 
Published: September 2017

Background and AimUlcerative colitis (UC) patients have several extraintestinal and systemic manifestations. As studies on the frequency and predictors of pulmonary involvement in patients with UC are inconsistent, we undertook this prospective study.MethodsEighty‐seven patients with UC (in remission 49, 56.3%, active disease 38, 43.6%, median age: 40 years, range: 16–66, 55, 62.2% males) and 50 healthy controls (median age: 38 years, range: 14–69, 34, 68% males) underwent pulmonary function tests (PFTs) including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), Tiffeneau value (FEV1/FVC), mid‐expiratory flow rate, and diffusion lung capacity for carbon monoxide with spirometer.ResultsSubjects with UC and control were comparable in age and gender. PFT was abnormal in 24 (27.5%) patients (active disease 15/38, 39.4%, remission 9/49, 18.4%) and 1 (2%) control (P < 0.005). Of the 24 patients with abnormal PFT, small airway, restrictive, and obstructive defects were detected in 12 (50%), 11 (45.8%), and 1 (4.2%) patients, respectively. Patients with abnormal PFT more often had active disease (15/24, 62.5% vs 23/63, 36.5%; P = 0.03). No relation of PFT abnormalities was found with age, sex, duration of disease, body mass index, serum albumin, and hemoglobin levels, and other extraintestinal manifestation (arthritis/arthralgia) and drugs used to treat UC.ConclusionUC patients with active disease have abnormal pulmonary functions with predominant involvement of small airways. Active UC was more often associated with abnormal PFT than the disease in remission.
Tight bounds for the vertices of degree k in minimally k‐connected graphs
Authors: Schmidt Jens M. 
Published: September 2017

AbstractFor minimally k‐connected graphs on n vertices, Mader proved a tight lower bound for the number of vertices of degree k in dependence on n and k. Oxley observed 1981 that in many cases a considerably better bound can be given if is used as additional parameter, i.e. in dependence on m, n, and k. It was left open to determine whether Oxley's more general bound is best possible. We show that this is not the case, but give a closely related bound that deviates from a variant of Oxley's long‐standing one only for small values of m. We prove that this new bound is best possible. The bound contains Mader's bound as special case.
Animal models for studying the etiology and treatment of low back pain
Authors: Shi Changgui , Qiu Sujun , Riester Scott M. , Das Vaskar , Zhu Bingqian , Wallace Atiyayein A. , van Wijnen Andre J. , Mwale Fackson , Iatridis James C. , Sakai Daisuke , Votta‐Velis Gina , Yuan Wen , Im Hee‐Jeong 
Published: September 2017

ABSTRACTChronic low back pain is a major cause of disability and health care costs. Effective treatments are inadequate for many patients. Animal models are essential to further understanding of the pain mechanism and testing potential therapies. Currently, a number of preclinical models have been developed attempting to mimic aspects of clinical conditions that contribute to low back pain (LBP). This review focused on describing these animal models and the main behavioral tests for assessing pain in each model. Animal models of LBP can be divided into the following five categories: Discogenic LBP, radicular back pain, facet joint osteoarthritis back pain, muscle‐induced LBP, and spontaneous occurring LBP models. These models are important not only for enhancing our knowledge of how LBP is generated, but also for the development of novel therapeutic regimens to treat LBP in patients. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1305–1312, 2018.
Elevated solute transport at sites of diffuse matrix damage in cortical bone: Implications on bone repair
Authors: Wang Bin , Sun Xuanhao , Akkus Ozan , Wang Liyun 
Published: September 2017

ABSTRACTDiffuse matrix damage in rat cortical bone has been observed to self‐repair efficiently in 2 weeks without activating bone remodeling, and unlike the case with linear cracks, the local osteocytes at the sites of diffuse damage remain healthy. However, the reason(s) for such high efficiency of matrix repair remains unclear. We hypothesized that transport of minerals and other compounds essential for damage repair is enhanced at the damaged sites and further increased by the application of tensile loading. To test our hypothesis, diffuse damage was introduced in notched bovine wafers under cyclic tensile loading and unloading. Using the Fluorescence Recovery After Photobleaching (FRAP) approach, we measured the transport of a small fluorescent tracer (sodium fluorescein, 376 Da) in damaged versus undamaged regions and under varying tensile load magnitudes (0.2 N, 10 N, 20 N, and 30 N), which corresponded to nominal strains of 12.5, 625, 1,250, and 1,875 microstrains, respectively. We found a 37% increase in transport of fluorescein in damaged regions relative to undamaged regions and a further ∼18% increase in transport under 20 N and 30 N tension compared to the non‐loaded condition, possibly due to the opening of the cracking surfaces. The elevated transport of minerals and other adhesive proteins may, at least partially, account for the highly effective repair of diffuse damage observed in vivo. Clinical Significance: Diffuse damage adversely affects bone's fracture resistance and this study provided quantitative data on elevated transport, which may be involved in repairing diffuse damage in vivo. 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:692–698, 2018.
Surgery for T4 lung cancer invading the thoracic aorta: Do we push the limits?
Authors: Marulli Giuseppe , Rendina Erino A. , Klepetko Walter , Perkmann Reinhold , Zampieri Davide , Maurizi Giulio , Klikovits Thomas , Zaraca Francesco , Venuta Federico , Perissinotto Egle , Rea Federico 
Published: September 2017

BackgroundFew investigators have described en bloc resection of non‐small cell lung cancer (NSCLC) invading the aorta.Aim of StudyAnalysis of outcome and prognostic factors for en bloc resections of NSCLC invading the aorta.MethodsThirty‐five patients (27 males, 8 females; mean age 63 ± 8.6 years) were operated between 1994 and 2015 in four European Centers. Histology: 12 (34.3%) squamous cell carcinoma, and 6 (17.1%) undifferentiated/large cell carcinoma. The site of aortic infiltration was the descending thoracic aorta in 24 (68.6%) patients, the aortic arch in 9 (25.7%), and the aortic arch and supraortic trunks in 2 (5.7%).ResultsLung resection consisted of pneumonectomy in 19 (54.3%) patients and lobectomy in 16 (45.7%). Aortic resection management was undertaken by endograft positioning (37.1%), subadventitial dissection (37.1%), cardiopulmonary/aorto‐aortic bypass (17.2%), and direct clamping (8.6%). A tubular graft replacement was carried out in five cases, a synthetic patch repair in 6. Mortality was 2.9%, morbidity 37.1%. Patients undergoing pneumonectomy had a significantly higher morbidity rate compared with lobectomy (52% vs 18.7%; P = 0.003), although patients managed with aortic endografting had a lower complication rate. Median overall and disease‐free survival rates were 31.3 and 22.2 months, respectively. Gender and site of aortic infiltration were independent prognostic factors.ConclusionsResection of NSCLC combined with an infiltrated aorta is a challenging procedure that can be performed with reasonable morbidity and mortality in highly selected patients.
Advances of OCT Technology for Laser Beam Processing
Authors: Dupriez Nataliya Deyneka , Denkl Alexander 
Published: September 2017

AbstractOptical coherence tomography (OCT) is an innovative sensor 3D measuring system for automated laser processing, in particular laser welding. It facilitates laser beam positioning, process monitoring, and quality control with the required precision and guarantees process flexibility, stability, and trace‐ability. To ensure smooth seam tracking for time‐ and cost‐effective line production, Lessmüller Lasertechnik OCT systems offer the automated recognition and digitalization of joints for precise lateral and axial positioning. It provides industrial solutions for the online inspection of the keyhole to enable consistent and high quality welds.
The land–sea interface: A source of high‐quality phytoplankton to support secondary production
Authors: Winder Monika , Carstensen Jacob , Galloway Aaron W. E. , Jakobsen Hans H. , Cloern James E. 
Published: September 2017

AbstractCoastal‐estuarine systems are among the most productive marine ecosystems and their special role in producing harvestable fish and shellfish has been attributed to high primary production fueled by nutrient runoff from land and efficient trophic transfer. Here we ask if phytoplankton species composition and their food quality based on the percentage of long‐chain essential fatty acids (LCEFA) is another factor contributing to high secondary production in these ecosystems. We used long‐term measurements of major phytoplankton taxonomic groups and estimated their content of LCEFA along the salinity gradient in coastal‐estuarine ecosystems, with emphasis on Chesapeake Bay and the Baltic Sea, and an oceanic transect. Our data show that cyanobacteria with low nutritional quality often dominate at low‐salinity regions, while intermediate to higher salinity regions produce diatoms and dinoflagellates that have a higher content of LCEFA and are thus a higher‐quality food resource for consumers. Higher salinity regions have less pronounced seasonal changes in the percentage of phytoplankton LCEFA compared to low salinity regions, providing a stable supply of nutritious phytoplankton to consumers. The phytoplankton LCEFA content is similarly high in coastal upwelling systems and it decreases further offshore in oligotrophic oceanic regions dominated by picophytoplankton. Our results from a broad range of coastal‐ecosystem types show that ecosystems at the land‐sea interface provide a valuable service by producing phytoplankton enriched in the biochemicals essential for consumers. High primary production, coupled with high quality of that production, explain why the production of fish and shellfish is high where land and sea meet.
Zinc isotope fractionation by Emiliania huxleyi cultured across a range of free zinc ion concentrations
Authors: Samanta Moneesha , Ellwood Michael J. , Strzepek Robert F. 
Published: September 2017

AbstractZinc (Zn) isotope fractionation by the coccolithophore Emiliania huxleyi (a Tasman Sea isolate) was investigated by culturing it across a range of free Zn2+ ion concentrations (1.2 pmol L−1 to 3.2 nmol L−1), which span the natural range observed in the global oceans. Across the range of free Zn2+ ion concentrations tested, the amount of bio‐available Zn did not have any appreciable influence on the specific growth rate or cell morphology of E. huxleyi. However, a suite of secondary physiological indicators reflected changes in Zn bioavailability. An increase in the photosynthetic efficiency of photosystem II (Fv/Fm) was observed with increasing free Zn2+ ion concentration. The time constants for electron transport from QA to QB and from QB to the plastoquinone (PQ) pool decreased as the free Zn2+ ion concentration increased, reflecting enhanced photosynthetic electron transport. The effect of Zn bioavailability on photosynthetic physiology was speculated to be due to increased activity of carbonic anhydrase with increasing Zn bioavailability. Zinc uptake by E. huxleyi resulted in Zn isotope fractionation and the Δ66Zncells‐media ranged between −0.6‰ and −0.2‰. The major finding from this work is that the lighter Zn isotope is taken up preferentially by this coccolithophore, making the dissolved Zn composition of the surrounding seawater isotopically heavier.
N2 fixation and primary productivity in a red sea Halophila stipulacea meadow exposed to seasonality
Authors: Cardini U. , van Hoytema N. , Bednarz V. N. , Al‐Rshaidat M. M. D. , Wild C. 
Published: September 2017

AbstractThe tropical seagrass Halophila stipulacea exhibits a limited capacity to use nitrate, but has a high uptake capacity and efficiency for ammonium. Consequently, N2 fixation by associated diazotrophic epiphytes may be important in providing ammonium needed for seagrass photosynthesis and growth. When exposed to seasonality, this association could provide a competitive advantage for H. stipulacea in relation to other seagrass species, but related knowledge is scarce. Here, we thus report measurements of net photosynthesis (O2 fluxes) and N2 fixation (acetylene reduction) associated with H. stipulacea from the Northern Red Sea over all four seasons of 2013. In parallel, we characterized the seagrass meadow areal extent, shoot and leaves density, and the leaf area index. Using this data, we quantified meadow net primary production and N2 fixation and estimated the photo‐metabolic N demand met by N2 fixation at the community level. Results revealed a marked seasonality of meadow N2 fixation, with rates ranging from 0.06 in winter to 4.60 mmol N m−2 d−1 in summer, i.e., an increase by two orders of magnitude. In summer, when nutrient concentrations in the water column were lowest and light intensity and temperature highest, there was a significant positive linear relationship between meadow net primary production and N2 fixation, with the latter accounting for ca. 20% of the photo‐metabolic N demand. These findings suggest that N2 fixation by associated diazotrophic epiphytes can mitigate N limitation of H. stipulacea meadows under N scarcity. This trait may also favor the ongoing geographical expansion of H. stipulacea.
Polymer Cancerostatics Targeted with an Antibody Fragment Bound via a Coiled Coil Motif: In Vivo Therapeutic Efficacy against Murine BCL1 Leukemia
Authors: Pechar Michal , Pola Robert , Janoušková Olga , Sieglová Irena , Král Vlastimil , Fábry Milan , Tomalová Barbora , Kovář Marek 
Published: September 2017

AbstractA BCL1 leukemia‐cell‐targeted polymer–drug conjugate with a narrow molecular weight distribution consisting of an N‐(2‐hydroxypropyl)methacrylamide copolymer carrier and the anticancer drug pirarubicin is prepared by controlled radical copolymerization followed by metal‐free click chemistry. A targeting recombinant single chain antibody fragment (scFv) derived from a B1 monoclonal antibody is attached noncovalently to the polymer carrier via a coiled coil interaction between two complementary peptides. Two pairs of coiled coil forming peptides (abbreviated KEK/EKE and KSK/ESE) are used as linkers between the polymer–pirarubicin conjugate and the targeting protein. The targeted polymer conjugate with the coiled coil linker KSK/ESE exhibits 4× better cell binding activity and 2× higher cytotoxicity in vitro compared with the other conjugate. Treatment of mice with established BCL1 leukemia using the scFv‐targeted polymer conjugate leads to a markedly prolonged survival time of the experimental animals compared with the treatment using the free drug and the nontargeted polymer–pirarubicin conjugate.