bluuebunny/crossref_metadata_2025 huggingface dataset:
Disruption of perineuronal nets increases the frequency of sharp wave ripple events
Authors: Sun Zhi Yong , Bozzelli P. Lorenzo , Caccavano Adam , Allen Megan , Balmuth Jason , Vicini Stefano , Wu Jian‐Young , Conant Katherine
Published: September 2017

Hippocampal sharp wave ripples (SWRs) represent irregularly occurring synchronous neuronal population events that are observed during phases of rest and slow wave sleep. SWR activity that follows learning involves sequential replay of training‐associated neuronal assemblies and is critical for systems level memory consolidation. SWRs are initiated by CA2 or CA3 pyramidal cells (PCs) and require initial excitation of CA1 PCs as well as participation of parvalbumin (PV) expressing fast spiking (FS) inhibitory interneurons. These interneurons are relatively unique in that they represent the major neuronal cell type known to be surrounded by perineuronal nets (PNNs), lattice like structures composed of a hyaluronin backbone that surround the cell soma and proximal dendrites. Though the function of the PNN is not completely understood, previous studies suggest it may serve to localize glutamatergic input to synaptic contacts and thus influence the activity of ensheathed cells. Noting that FS PV interneurons impact the activity of PCs thought to initiate SWRs, and that their activity is critical to ripple expression, we examine the effects of PNN integrity on SWR activity in the hippocampus. Extracellular recordings from the stratum radiatum of horizontal murine hippocampal hemisections demonstrate SWRs that occur spontaneously in CA1. As compared with vehicle, pre‐treatment (120 min) of paired hemislices with hyaluronidase, which cleaves the hyaluronin backbone of the PNN, decreases PNN integrity and increases SWR frequency. Pre‐treatment with chondroitinase, which cleaves PNN side chains, also increases SWR frequency. Together, these data contribute to an emerging appreciation of extracellular matrix as a regulator of neuronal plasticity and suggest that one function of mature perineuronal nets could be to modulate the frequency of SWR events.
Synthesis of Monothiomalonates – Versatile Thioester Enolate Equivalents for C–C Bond Formations
Authors: Engl Oliver D. , Saadi Jakub , Cosimi Elena , Wennemers Helma
Published: September 2017

Monothiomalonates (MTMs) are surrogates of thioester enolates that allow for stereoselective C–C bond formations under mild conditions and thereby afford access to synthetically versatile thioester derivatives. Here we present a straightforward synthetic route to MTMs that proceeds through nucleophilic ring‐opening of Meldrum's acid derivatives followed by O‐alkylation of the resulting malonic acid half thioesters with alkyl triflates or acetimidates as electrophiles. The method affords MTMs in overall yields of 34 – 92% and allows for variations of the oxo‐ and thioester moieties as well as the substituent at the C(α) position.
Dacomitinib‐induced diarrhea: Targeting chloride secretion with crofelemer
Authors: Van Sebille Ysabella Z.A. , Gibson Rachel J. , Wardill Hannah R. , Ball Imogen A. , Keefe Dorothy M.K. , Bowen Joanne M.
Published: September 2017

Dacomitinib, an irreversible small‐molecule pan‐ErbB TKI, has a high incidence of diarrhea, which has been suggested to be due to chloride secretory mechanisms. Based on this hypothesis, crofelemer, an antisecretory agent may be an effective intervention. T84 monolayers were treated with 1 µM dacomitinib and 10 µM crofelemer, and mounted into Ussing chambers for electrogenic ion analysis. Crofelemer attenuated increases in chloride secretion in cells treated with dacomitinib. Albino Wistar rats (n = 48) were treated with 7.5 mg/kg dacomitinib and/or 25 mg/kg crofelemer via oral gavage for 21 days. Crofelemer significantly worsened dacomitinib‐induced diarrhea (p = 0.0003), and did not attenuate weight loss (p < 0.0001). Sections of the ileum and colon were mounted into Ussing chambers, and secretory processes analyzed. This indicated that crofelemer lost its anti‐secretory action in the presence of dacomitinib in this model. Mass spectrometry revealed that crofelemer did not change serum concentration of dacomitinib. Serum FITC dextran levels indicated that crofelemer was unable to attenuate dacomitinib‐induced barrier dysfunction. Tight junction proteins were visualized with immunofluorescence. Qualitative analysis showed dacomitinib induced proteolysis of ZO‐1 and occludin, and internalization of claudin‐1, which was not attenuated by crofelemer. Detailed histopathological analysis showed that crofelemer was unable to attenuate dacomitinib‐induced ileal damage. Crofelemer worsened dacomitinib‐induced diarrhea, suggesting that antisecretory drug therapy may be ineffective in this setting.
The impact of P‐glycoprotein and breast cancer resistance protein on the brain pharmacokinetics and pharmacodynamics of a panel of MEK inhibitors
Authors: de Gooijer Mark C. , Zhang Ping , Weijer Ruud , Buil Levi C.M. , Beijnen Jos H. , van Tellingen Olaf
Published: September 2017

Mitogen/extracellular signal‐regulated kinase (MEK) inhibitors have been tested in clinical trials for treatment of intracranial neoplasms, including glioblastoma (GBM), but efficacy of these drugs has not yet been demonstrated. The blood‐brain barrier (BBB) is a major impediment to adequate delivery of drugs into the brain and may thereby also limit the successful implementation of MEK inhibitors against intracranial malignancies. The BBB is equipped with a range of ATP‐dependent efflux transport proteins, of which P‐gp (ABCB1) and BCRP (ABCG2) are the two most dominant for drug efflux from the brain. We investigated their impact on the pharmacokinetics and target engagement of a panel of clinically applied MEK inhibitors, in order to select the most promising candidate for brain cancers in the context of clinical pharmacokinetics and inhibitor characteristics. To this end, we used in vitro drug transport assays and conducted pharmacokinetic and pharmacodynamic studies in wildtype and ABC‐transporter knockout mice. PD0325901 displayed more promising characteristics than trametinib (GSK1120212), binimetinib (MEK162), selumetinib (AZD6244), and pimasertib (AS703026): PD0325901 was the weakest substrate of P‐gp and BCRP in vitro, its brain penetration was only marginally higher in Abcb1a/b;Abcg2−/− mice, and efficient target inhibition in the brain could be achieved at clinically relevant plasma levels. Notably, target inhibition could also be demonstrated for selumetinib, but only at plasma levels far above levels in patients receiving the maximum tolerated dose. In summary, our study recommends further development of PD0325901 for the treatment of intracranial neoplasms.
Tumor‐suppressive miR‐145 co‐repressed by TCF4‐β‐catenin and PRC2 complexes forms double‐negative regulation loops with its negative regulators in colorectal cancer
Authors: Wang Wei , Xiao Xin , Chen Xu , Huo Yi , Xi Wen‐Jin , Lin Zhi‐Feng , Zhang Dan , Li Yu‐Fang , Yang Fan , Wen Wei‐Hong , Yang An‐Gang , Wang Tao
Published: September 2017

The frequently dysregulated Wnt/β‐catenin signaling in different malignancies, by activation of its own or orchestration with other co‐factors, regulates various oncogenic or tumor‐suppressive genes. Among these genes, miRNAs, which are negative posttranscriptional regulators, are also embedded in the Wnt signaling network. Different from the Wnt‐induced oncogenic miRNAs, the specific mechanism underlying the Wnt‐repressed tumor‐suppressive miRNAs is much less understood. In our study, firstly by analyzing a ChIP‐seq dataset against TCF4, the core transcription factor for initiation of Wnt signaling in colorectal cancer (CRC) cells, we screened out several tumor‐suppressive miRNAs potentially regulated by Wnt signaling. Then through siRNA‐mediated knock‐down tests and protein and chromatin immunoprecipitations, we found the TCF4‐β‐catenin complex can recruit the histone trimethylation complex PRC2 as a co‐repressor while binding to the TCF4‐binding element (TBE) in the promoter regions of miR‐145, miR‐132 and miR‐212. Thus, upon Wnt signaling activation, the PRC2‐mediated trimethylation of histone H3 at lysine 27 increases at these promoter regions, leading to decreased miRNA levels. Furthermore, we found that by targeting TCF4 and SUZ12, the key components of the negative regulation complexes, the tumor‐suppressive miR‐145 co‐repressed by Wnt signaling and histone trimethylation, forms double‐negative regulation loops with its negative regulators in CRC cells. And the inverse associations between miR‐145 and its targets/negative regulators have also been demonstrated in nude mice and clinical samples. Collectively, we elucidated the detailed molecular mechanism of how dysregulated Wnt/β‐catenin signaling and tumor‐suppressive miRNAs reciprocally regulate each other in CRC cells.
NFATC1 activation by DNA hypomethylation in chronic lymphocytic leukemia correlates with clinical staging and can be inhibited by ibrutinib
Authors: Wolf Christine , Garding Angela , Filarsky Katharina , Bahlo Jasmin , Robrecht Sandra , Becker Natalia , Zucknick Manuela , Rouhi Arefeh , Weigel Anja , Claus Rainer , Weichenhan Dieter , Eichhorst Barbara , Fischer Kirsten , Hallek Michael , Kuchenbauer Florian , Plass Christoph , Döhner Hartmut , Stilgenbauer Stephan , Lichter Peter , Mertens Daniel
Published: September 2017

B cell receptor (BCR) signaling is a key for survival of chronic lymphocytic leukemia (CLL) cells, and BCR signaling inhibitors are clinically active. However, relapse and resistance to treatment require novel treatment options. To detect novel candidate therapeutic targets, we performed a genome‐wide DNA methylation screen with custom arrays and identified aberrant promoter DNA methylation in 2,192 genes. The transcription factor NFATC1 that is a downstream effector of BCR signaling was among the top hypomethylated genes and was concomitantly transcriptionally upregulated in CLL. Intriguingly, NFATC1 promoter DNA hypomethylation levels were significantly variant in clinical trial cohorts from different disease progression stages and furthermore correlated with Binet disease staging and thymidine kinase levels, strongly suggesting a central role of NFATC1 in CLL development. Functionally, DNA hypomethylation at NFATC1 promoter inversely correlated with RNA levels of NFATC1 and dysregulation correlated with expression of target genes BCL‐2, CCND1 and CCR7. The inhibition of the NFAT regulator calcineurin with tacrolimus and cyclosporin A and the BCR signaling inhibitor ibrutinib significantly reduced NFAT activity in leukemic cell lines, and NFAT inhibition resulted in increased apoptosis of primary CLL cells. In summary, our results indicate that the aberrant activation of NFATC1 by DNA hypomethylation and BCR signaling plays a major role in the pathomechanism of CLL.
Construction of human induced pluripotent stem cell‐derived oriented bone matrix microstructure by using in vitro engineered anisotropic culture model
Authors: Ozasa Ryosuke , Matsugaki Aira , Isobe Yoshihiro , Saku Taro , Yun Hui‐Suk , Nakano Takayoshi
Published: September 2017

Bone tissue has anisotropic microstructure based on collagen/biological apatite orientation, which plays essential roles in the mechanical and biological functions of bone. However, obtaining an appropriate anisotropic microstructure during the bone regeneration process remains a great challenging. A powerful strategy for the control of both differentiation and structural development of newly‐formed bone is required in bone tissue engineering, in order to realize functional bone tissue regeneration. In this study, we developed a novel anisotropic culture model by combining human induced pluripotent stem cells (hiPSCs) and artificially‐controlled oriented collagen scaffold. The oriented collagen scaffold allowed hiPSCs‐derived osteoblast alignment and further construction of anisotropic bone matrix which mimics the bone tissue microstructure. To the best of our knowledge, this is the first report showing the construction of bone mimetic anisotropic bone matrix microstructure from hiPSCs. Moreover, we demonstrated for the first time that the hiPSCs‐derived osteoblasts possess a high level of intact functionality to regulate cell alignment. © 2017 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 360–369, 2018.
Surface modification of ultrahigh molecular weight polyethylene by plasma‐induced in‐situ grafting with vinyl triethoxysilane
Authors: Meng Chenbo , Chen Yangmei , Xie Meiju , Yu Zili , Yang Bangcheng
Published: September 2017

Ultrahigh molecular weight polyethylene (UHMWPE) is an excellent material with high performance, but it is very difficult to covalently introduce functional groups on its surface owing to its inherently inert structure, which constrains its further application. In this study, vinyl triethoxysilane (VTEOS) containing hydrolysable alkoxyl groups was in situ grafted on UHMWPE by air plasma treatment. The plasma treatment conditions for VTEOS grafting were optimized. The structure of the modified UHMWPE was characterized with FTIR and XPS. The relatively high VTEOS content was obtained when the treating conditions were about 20 W, 125 Pa for 10 min. And FTIR results showed that the grafted structure on the surface was stable for long time duration in the ambient environment. After the treatment, the roughness of the surface increased and the water contact angle of the modified sample dropped to 47.5° from 92.8° of the unmodified one. TGA and XRD results indicated that plasma treatment would not change the bulk structure of UHMWPE greatly. Cell culture experiments showed that fibroblasts on the modified samples had notably high viability and proliferation rate with good adhesion shape. Hence, it might be an effective method to improve the surface properties of UHMWPE for biomedical applications by plasma‐induced in‐situ grafting with VTEOS. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 321–332, 2018.
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

Immuno‐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

The 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 Aim

Anti‐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.

Methods

This 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.

Results

Thirty‐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.

Conclusion

Higher 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 Aim

Capsule 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.

Methods

Retrospective 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.

Results

A 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.

Conclusions

CE 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 Aim

Ulcerative 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.

Methods

Eighty‐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.

Results

Subjects 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.

Conclusion

UC 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

For 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.
Molecular dynamics simulation revealed binding of nucleotide inhibitors to ZIKV polymerase over 444 nanoseconds
Authors: Elfiky Abdo A. , Elshemey Wael M.
Published: September 2017

In the year 2015, new Zika virus (ZIKV) broke out in Brazil and spread away in more than 80 countries. Scientists directed their efforts toward viral polymerase in attempt to find inhibitors that might interfere with its function. In this study, molecular dynamics simulation (MDS) was performed over 444 ns for a ZIKV polymerase model. Molecular docking (MD) was then performed every 10 ns during the MDS course to ensure the binding of small molecules to the polymerase over the entire time of the simulation. MD revealed the binding ability of four suggested guanosine inhibitors (GIs); (Guanosine substituted with OH and SH (phenyl) oxidanyl in the 2′ carbon of the ribose ring). The GIs were compared to guanosine triphosphate (GTP) and five anti‐hepatitis C virus drugs (either approved or under clinical trials). The mode of binding and the binding performance of GIs to ZIKV polymerase were found to be the same as GTP. Hence, these compounds were capable of competing GTP for the active site. Moreover, GIs bound to ZIKV active site more tightly compared to ribavirin, the wide‐range antiviral drug.
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

Chronic 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

Diffuse 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

Background

Few investigators have described en bloc resection of non‐small cell lung cancer (NSCLC) invading the aorta.

Aim of Study

Analysis of outcome and prognostic factors for en bloc resections of NSCLC invading the aorta.

Methods

Thirty‐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%).

Results

Lung 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.

Conclusions

Resection 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

Optical 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

Coastal‐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

Zinc (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

The 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.
UNDERSTAND WHAT MOTIVATES EACH PERSON ON YOUR TEAM
Authors: Scott Kim
Published: September 2017

Scott draws on her leadership experience at Google, Apple, and elsewhere to explain her concept of Radical Candor. This means people need to hear the truth for their own sake as well as that of the organization and their colleagues, but they need to hear it in the right way, to be properly understood and in the best interest of all. This is especially important given the interdependent nature of teams. She discusses how to discover and work with a person's growth trajectory, taking into account whether it is steep or gradual. She writes: “People evolve, so your relationships must evolve with them. Care personally; don't put people in boxes and leave them there.”
TO GRIND YOUR SPARKS AND SPARK YOUR GRIND, EMBRACE A ROUTINE
Authors: Wahl Erik
Published: September 2017

A unique view of the creative process is provided by the artist, author, and entrepreneur Wahl. He describes the long and circuitous route he took to becoming a successful artist, creating artwork onstage before large audiences. He offers guidance to others based on his own experience, including what to do when you begin having success with your creativity: “Start by looking at your ‘finished’ creations from all angles. How can you improve them? What about them isn't particularly original? What about them isn't signature you?” The goal is to use disciplined creativity to make great things, no matter what they are.
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

A 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.
Acrylate Network Formation by Free‐Radical Polymerization Modeled Using Random Graphs
Authors: Schamboeck Verena , Kryven Ivan , Iedema Pieter D.
Published: September 2017

A novel technique is developed to predict the evolving topology of a diacrylate polymer network under photocuring conditions, covering the low‐viscous initial state to full transition into polymer gel. The model is based on a new graph theoretical concept being introduced in the framework of population balance equations (PBEs) for monomer states (mPBEs). A trivariate degree distribution that describes the topology of the network locally is obtained from the mPBE, which serves as an input for a directional random graph model. Thus, access is granted to global properties of the acrylate network which include molecular size distribution, distributions of molecules with a specific number of crosslinks/radicals, gelation time/conversion, and gel/sol weight fraction. Furthermore, an analytic criterion for gelation is derived. This criterion connects weight fractions of converted monomers and the transition into the gel regime. Valid results in both sol and gel regimes are obtained by the new model, which is confirmed by a comparison with a “classical” macromolecular PBE model. The model predicts full transition of polymer into gel at very low vinyl conversion (<2%). Typically, this low‐conversion network is very sparse, as becomes apparent from the predicted crosslink distribution.
Simulating Light Scattering Behavior of Branched Molecules
Authors: Tacx Jacques C. J. F. , Iedema Piet D.
Published: September 2017

Monte Carlo simulations reveal long chain branching (LCB) topology based on kinetics of systems like low‐density polyethylene (ldPE). Examining the topologies computed shows the majority of branch arms to be short as compared to backbone length, while also a significant branch‐on‐branch fine structure is observed. Until now, predicting scattering functionP−1(θ) from LCB has only been successful for structures like simple combs or stars. Topologies in graph theoretical form are used to predict scattering functionP−1(θ) andby summating intramolecular distances, accounting for branching and excluded volume. Experimental size exclusion chromatography with multiangle light scattering can be brought in line with the predicted branching character. Branching is less than predicted due to a different fine structure in ldPE leading to stronger size contraction.
An efficient method for fractional nonlinear differential equations by quasi‐Newton's method and simplified reproducing kernel method
Authors: Xu Minqiang , Niu Jing , Lin Yingzhen
Published: September 2017

An efficient method for nonlinear fractional differential equations is proposed in this paper. This method consists of 2 steps. First, we linearize the nonlinear operator equation by quasi‐Newton's method, which is based on Fréchet derivative. Then we solve the linear fractional differential equations by the simplified reproducing kernel method. The convergence of the quasi‐Newton's method is discussed for the general nonlinear case as well. Finally, some numerical examples are presented to illustrate accuracy, efficiency, and simplicity of the method.
Technical Note: A simple algorithm to convert EPID gray values into absorbed dose to water without prior knowledge
Authors: Boutry Christine , Sors Aurélie , Fontaine Jimmy , Delaby Nolwenn , Delpon Gregory
Published: September 2017

Purpose

Full integration of EPID‐based dosimetry in a global quality control workflow is still complicated. All the actual solutions are based on a relation between image gray‐level signal and total linac‐delivered dose. In this study, we propose a simple algorithm relying pixel gray‐level of EPID image with average linac delivered dose per acquisition frame.

Methods

Calibration models are constructed for Varian and Elekta linacs including scattering conditions and EPID‐arm backscatter‐specific corrections. Only simple homogeneous fields are required to establish the EPID dose conversion model for each x‐ray beam. Then, the model was evaluated by comparing calculated and converted dose distributions for homogeneous and modulated beams using gamma maps.

Results

To fit average dose per frame (Dfnorm) vs pixel gray value (Ngnorm) of each EPID image, a logarithmic curve , has been chosen where A, B and C are constants depending on beam energy. Gamma comparison (2%, 2 mm, threshold 15%) between converted images and calculated dose distributions for linac control and pretreatment patient fields led to a gamma pass rate higher than 97% for all the analyzed fields.

Conclusions

Without a prior irradiation settings knowledge except the incident energy beam, we use EPID as a reliable dose to water detector for both homogeneous and modulated beams.
Machine‐specific quality assurance procedure for stereotactic treatments with dynamic couch rotations
Authors: Wilson Byron , Gete Ermias
Published: September 2017

Objective

We present a method in which the treatment couch's accuracy is measured using the electronic portal imaging device (EPID) and a phantom of our own construction. Using this phantom, we were able to quantify the treatment couch walkout, and the rotation angle accuracy for both static and dynamic couch treatments. These measurements were used to provide an accurate measure of the treatment couch isocenter as well as to verify the couch rotation angle recorded in the trajectory log.

Methods

The phantom was constructed using a polystyrene slab in which five ball bearings of 4 mm diameter are placed on the same plane at varying radii (0, 2.8, 4.4, 5.6, and 6.7 cm). The couch was rotated through its full extent (‐90, 90 degrees) while MV images were acquired continuously. The couch rotational accuracy was calculated using a least squares minimization which fit the locations of the BBs to their expected locations relative to reference setup conditions. Using this approach, rotation angle and isocenter walkout was calculated in three dimensions. These measurements were used to quantify the accuracy of the couch as well as to validate the Varian TrueBeam trajectory logs. Additionally, a method for an EPID‐based couch star‐shot measurement was developed and compared with the traditional film‐based method.

Results

The measured couch center of rotation consisted of a cloud of points clustered around the room isocenter within 0.7 mm distance. The trajectory log couch angle values agreed with those recorded in the DICOM header of the EPID images to the third significant digit and the couch rotation angles recorded in the trajectory log and DICOM header agreed with the calculated values to 0.08 degrees. Comparison of couch star‐shot measurement developed in this study with film‐based star‐shot measurements gave an agreement to within 0.2 mm.

Conclusion

We have developed a quality assurance method for the treatment couch which is simple, accurate, and enables the user to access a multitude of consistent data with a single measurement. Using this method, we have shown that the treatment couch is accurate for both static and dynamic stereotactic deliveries.