bluuebunny/crossref_metadata_2025 huggingface dataset:
Neoplasms of the Vulva and Vagina
Authors: Dewdney Summer B. , Rotmensch Jacob
Published: March 2017

Overview

Vulvar and vaginal carcinomas are uncommon diseases that generally affect post‐menopausal women, although 19% of vulvar carcinomas occur in women >50 years old. Risk factors for vulvar cancer include human papilloma virus and chronic inflammation. Vulvar intraepithelial neoplasia can often be managed with wide local excision, but several other modalities have been utilized. Most vulvar malignancies are squamous cell carcinomas that are managed by surgical excision and radiotherapy. Sentinel lymph node biopsy has been used to spare the morbidity observed after regional lymph node dissection. For more advanced lesions, chemo‐radiotherapy with agents such as 5‐FU, cisplatin, and mitomycin C is utilized. Other vulvar malignancies include Bartholin gland carcinomas, basal cell carcinomas, verrucous carcinomas, and melanomas. Carcinomas of the vagina are most frequently squamous cell, but clear cell adenocarcinomas have been seen in younger women. In the past, clear cell carcinomas were associated with prenatal exposure to diethyl‐stibestrol. Vaginal melanomas can occur, as well as endodermal sinus tumors, rhrabdomysarcomas, and fibroepithelial vagina polyps.
Endometrial Cancer
Authors: Rahaman Jamal , Lu Karen , Cohen Carmel J.
Published: March 2017

Overview

Endometrial carcinoma is the most frequent gynecologic cancer in the United States with over 50,000 new cases diagnosed per year. Over 80% have Type I cancers with the classic estrogen‐dependent endometrioid histology and a favorable prognosis. Type II cancers have a different molecular profile associated with more virulent disease and diminished survival and include uterine serous papillary carcinomas (UPSC) and clear cell carcinomas. The Cancer Genome Atlas (TCGA) has recently defined four molecular subtypes of endometrial cancer based on somatic mutations, copy number alterations, and microsatellite instability status. Over 75% of patients are present with irregular or postmenopausal bleeding. Surgical staging includes a total hysterectomy, bilateral salpingo‐oophorectomy, and pelvic and para‐aortic lymph node sampling, which can be performed via a laparotomy, laparoscopy, or robotic surgery. Surgery, where possible, constitutes the definitive primary treatment for most patients with endometrial carcinoma. Primary radiation therapy and primary hormonal therapy are alternatives for inoperable patients. Adjuvant therapy for Stage I disease is determined by age, depth of myometrial invasion, lymphovascular space invasion, and tumor grade. For patients with advanced and recurrent disease, radiation therapy, chemotherapy, and hormonal therapy are utilized. Paclitaxel (T), carboplatin (C), cisplatin (P), and doxorubicin (A) are the most active single agents with TC and TAP being the most effective combination of chemotherapy regimens. Hormonal therapy includes oral progestins, the progesterone‐containing intrauterine device, tamoxifen, gonadotropin‐releasing hormone analogs, and aromatase inhibitors. Emerging biologic agents with activity include bevacizumab and mTOR inhibitors. Tumor molecular profiling, minimal invasive surgery, sentinel lymph node assessment, and integration of novel biologic therapies will likely play a greater role in the future.
Coagulopathic Complications of Cancer Patients
Authors: De Sancho Maria T. , Rand Jacob H.
Published: March 2017

Overview

Bleeding and thrombotic complications are common in cancer patients. The bleeding complications usually result from abnormalities in platelets or deficiency of coagulation factors and require specific blood or coagulation factor replacement. Thromboembolic events including deep venous thrombosis and pulmonary embolism are common and associated with serious complications. New biomarkers, diagnostic imaging approached and anticoagulant therapies have significantly improved the care of these patients. Ongoing research in the understanding of the various disturbances in hemostasis, application of innovative treatment modalities, and use of appropriate thromboprophylaxis in cancer patients should lead to further decreased morbidity and improved survival.
Cardiac Complications
Authors: Ewer Michael S. , Ewer Steven M. , Suter Thomas
Published: March 2017

Overview

Patients with malignant diseases often have coexisting cardiovascular disorders or may face serious cardiovascular complications in the course of their disease. The disorders may result from underlying conditions such as atherosclerosis, hypertension, or valvular abnormalities, or they may result directly from cancer or its treatment (Table 1). In addition, cardiovascular disorders that are unusual in patients not afflicted with cancer may be more common in the cancer patient and sometimes are unsuspected. Furthermore, cardiovascular diseases common in the general population must not be overlooked in patients with cancer; the presentation of such entities may be unusual, and the diagnosis often is more complex. Increased clinical scrutiny is therefore necessary in this vulnerable population. Multiple clinical problems may also coexist and defy a simple illumination because of the complex interactions between the malignancy, its treatment, and the cardiovascular system; what affects one often alters the presentation and course of the others. This chapter will look at some of the more common cardiovascular complications of cancer and its treatment, and will also address some of the dilemmas encountered in cancer patients with concomitant cardiac conditions.
Oral Complications of Cancer and Their Treatment
Authors: Sonis Stephen T. , Yuan Anna
Published: March 2017

Overview

The mouth is a frequent site of direct and indirect adverse side effects of cancer therapy. In myelosuppressed patients, its diverse microbiota makes the oral cavity both a site of local infection and a potential source of bacteremias and sepsis. While about half of all patients being treated with chemotherapy or radiation therapy will develop some form of oral toxicity or infection, almost every patient receiving an aggressive myeloablative regimen or local radiotherapy to the head and neck manifests acute and chronic toxicities. The diversity of the tissues found in and around the mouth—keratinized and nonkeratinized mucosa, bone, salivary glands, and teeth—contributes to the range of susceptibility, acuity, and clinical implications of regimen‐related oral complications. In almost all instances, precancer treatment elimination or control of existing oral diseases and aggressive management of oral health during cancer therapy favorably impacts outcomes.
Lung volume reproducibility under ABC control and self‐sustained breath‐holding
Authors: Kaza Evangelia , Dunlop Alex , Panek Rafal , Collins David J. , Orton Matthew , Symonds‐Tayler Richard , McQuaid Dualta , Scurr Erica , Hansen Vibeke , Leach Martin O.
Published: March 2017

An Active Breathing Coordinator (ABC) can be employed to induce breath‐holds during CT imaging and radiotherapy of lung, breast and liver cancer, and recently during lung cancer MRI. The apparatus measures and controls respiratory volume, hence subject lung volume reproducibility is its principal measure of effectiveness. To assess ABC control quality, the intra‐session reproducibility of ABC‐induced lung volumes was evaluated and compared with that reached by applying the clinical standard of operator‐guided self‐sustained breath‐holds on healthy volunteers during MRI. Inter‐session reproducibility was investigated by repeating ABC‐controlled breath‐holds on a second visit. Additionally, lung volume agreement with ABC devices used with different imaging modalities in the same institution (MR, CT), or for a breast trial treatment, was assessed. Lung volumes were derived from three‐dimensional (3D) T1‐weighted MRI datasets by three observers employing semiautomatic lung delineation on a radiotherapy treatment planning system. Inter‐observer variability was less than 6% of the delineated lung volumes. Lung volume agreement between the different conditions over all subjects was investigated using descriptive statistics. The ABC equipment dedicated for MR application exhibited good intra‐session and inter‐session lung volume reproducibility (1.8% and 3% lung volume variability on average, respectively). MR‐assessed lung volumes were similar using different ABC equipment dedicated to MR, CT, or breast radiotherapy. Overall, lung volumes controlled by the same or different ABC devices agreed better than with self‐controlled breath‐holds, as suggested by the average ABC variation of 1.8% of the measured lung volumes (99 mL), compared to the 4.1% (226 mL) variability observed on average with self‐sustained breath‐holding.
Comparison of CT images with average intensity projection, free breathing, and mid‐ventilation for dose calculation in lung cancer
Authors: Khamfongkhruea Chirasak , Thongsawad Sangutid , Tannanonta Chirapha , Chamchod Sasikarn
Published: March 2017

The purpose of this study was to compare three computed tomography (CT) images under different conditions—average intensity projection (AIP), free breathing (FB), mid‐ventilation (MidV)—used for radiotherapy contouring and planning in lung cancer patients. Two image sets derived from four‐dimensional CT (4DCT) acquisition (AIP and MidV) and three‐dimensional CT with FB were generated and used to plan for 29 lung cancer patients. Organs at risk (OARs) were delineated for each image. AIP images were calculated with 3D conformal radiotherapy (3DCRT) and intensity‐modulated radiation therapy (IMRT). Planning with the same target coverage was applied to the FB and MidV image sets. Plans with small and large tumors were compared regarding OAR volumes, geometrical center differences in OARs, and dosimetric indices. A gamma index analysis was also performed to compare dose distributions. There were no significant differences (P > 0.05) in OAR volumes, the geometrical center differences, maximum and mean doses of the OARs between both tumor sizes. For 3DCRT, the gamma analysis results indicated an acceptable dose distribution agreement of 95% with 2%/2 mm criteria. Although, the gamma index results show distinct contrast of dose distribution outside the planning target volume (PTV) in IMRT, but within the PTV, it was acceptable. All three images could be used for OAR delineation and dose calculation in lung cancer. AIP image sets seemed to be suitable for dose calculation while patient movement between series acquisition of FB images should be considered when defining target volumes on 4DCT images.
Photon Optimizer (PO) prevails over Progressive Resolution Optimizer (PRO) for VMAT planning with or without knowledge‐based solution
Authors: Jiang Fan , Wu Hao , Yue Haizhen , Jia Fei , Zhang Yibao
Published: March 2017

The enhanced dosimetric performance of knowledge‐based volumetric modulated arc therapy (VMAT) planning might be jointly contributed by the patient‐specific optimization objectives, as estimated by the RapidPlan model, and by the potentially improved Photon Optimizer (PO) algorithm than the previous Progressive Resolution Optimizer (PRO) engine. As PO is mandatory for RapidPlan estimation but optional for conventional manual planning, appreciating the two optimizers may provide practical guidelines for the algorithm selection because knowledge‐based planning may not replace the current method completely in a short run. Using a previously validated dose–volume histogram (DVH) estimation model which can produce clinically acceptable plans automatically for rectal cancer patients without interactive manual adjustment, this study reoptimized 30 historically approved plans (referred as clinical plans that were created manually with PRO) with RapidPlan solution (PO plans). Then the PRO algorithm was utilized to optimize the plans again using the same dose–volume constraints as PO plans, where the line objectives were converted as a series of point objectives automatically (PRO plans). On the basis of comparable target dose coverage, the combined applications of new objectives and PO algorithm have significantly reduced the organs‐at‐risk (OAR) exposure by 23.49–32.72% than the clinical plans. These discrepancies have been largely preserved after substituting PRO for PO, indicating the dosimetric improvements were mostly attributable to the refined objectives. Therefore, Eclipse users of earlier versions may instantly benefit from adopting the model‐generated objectives from other RapidPlan‐equipped centers, even with PRO algorithm. However, the additional contribution made by the PO relative to PRO accounted for 1.54–3.74%, suggesting PO should be selected with priority whenever available, with or without RapidPlan solution as a purchasable package. Significantly increased monitor units were associated with the model‐generated objectives but independent from the optimizers, indicating higher modulation in these plans. As a summary, PO prevails over PRO algorithm for VMAT planning with or without knowledge‐based technique.
On the Microstructure Homogeneity of AA6061 Alloy After Cross‐Shear Deformations
Authors: Ko Young Gun , Hamad Kotiba
Published: March 2017

This work is presented to investigate the homogeneity of microstructures evolved after cross‐shear deformations imposed by a differential speed rolling (DSR) process. For this purpose, transmission electron microscopy (TEM) microstructures and through‐thickness hardness maps of AA6061 aluminum alloy samples deformed by the DSR process are investigated. The results reveal the evolution of ultrafine grained structures (≈0.3 µm) after DSR deformation. Additionally, it is found that the through‐thickness homogeneity is clearly improved as the number of the cross‐shear increases.
Scrutinizing Design Principles toward Efficient, Long‐Term Stable Green Light‐Emitting Electrochemical Cells
Authors: Namanga Jude E. , Gerlitzki Niels , Mudring Anja‐Verena
Published: March 2017

Enhancing the efficiency and lifetime of light emitting electrochemical cells (LEC) is the most important challenge on the way to energy efficient lighting devices of the future. To avail this, emissive Ir(III) complexes with fluoro‐substituted cyclometallated ligands and electron donating groups (methyl and tert‐butyl)‐substituted diimine ancillary (N^N) ligands and their associated LEC devices are studied. Four different complexes of general composition [Ir(4ppy)2(N^N)][PF6] (4Fppy = 2‐(4‐fluorophenyl)pyridine) with the N^N ligand being either 2,2′‐bipyridine (1), 4.4′‐dimethyl‐2,2′‐bipyridine (2), 5.5′‐dimethyl‐2,2′‐bipyridine (3), or 4.4′‐di‐tert‐butyl‐2,2′‐bipyridine (4) are synthesized and characterized. All complexes emit in the green region of light with emission maxima of 529–547 nm and photoluminescence quantum yields in the range of 50.6%–59.9%. LECs for electroluminescence studies are fabricated based on these complexes. The LEC based on (1) driven under pulsed current mode demonstrated the best performance, reaching a maximum luminance of 1605 cd m−2 resulting in 16 cd A−1 and 8.6 lm W−1 for current and power efficiency, respectively, and device lifetime of 668 h. Compared to this, LECs based on (3) and (4) perform lower, with luminance and lifetime of 1314 cd m−2, 45.7 h and 1193 cd m−2, 54.9 h, respectively. Interestingly, in contrast to common belief, the fluorine content of the Ir‐iTMCs does not adversely affect the LEC performance, but rather electron donating substituents on the N^N ligands are found to dramatically reduce both performance and stability of the green LECs. In light of this, design concepts for green light emitting electrochemical devices have to be reconsidered.
Highly Stable Conjugated Polyelectrolytes for Water‐Based Hybrid Mode Electrochemical Transistors
Authors: Zeglio Erica , Eriksson Jens , Gabrielsson Roger , Solin Niclas , Inganäs Olle
Published: March 2017

Hydrophobic, self‐doped conjugated polyelectrolytes (CPEs) are introduced as highly stable active materials for organic electrochemical transistors (OECTs). The hydrophobicity of CPEs renders films very stable in aqueous solutions. The devices operate at gate voltages around zero and show no signs of degradation when operated for 104 cycles under ambient conditions. These properties make the produced OECTs ideal devices for applications in bioelectronics.
Metal‐Free, TBHP‐Mediated, [3+2+1]‐Type Intermolecular Cycloaddition Reaction: Synthesis of Pyrimidines from Amidines, Ketones, and DMF through C(sp3)−H Activation
Authors: Zheng Lv‐Yin , Guo Wei , Fan Xiao‐Lin
Published: March 2017

An efficient method for the direct construction of pyrimidines from a metal‐free, TBHP‐mediated, [3+2+1]‐type intermolecular cycloaddition reaction from amidines, ketones, and DMF through C(sp3)−H activation has been developed. This transformation involves the formation of new C−C/C−N bonds and features sustainable oxidants, readily available starting materials, and high atom and step economies.
Equatorial Ligand Perturbations Influence the Reactivity of Manganese(IV)‐Oxo Complexes
Authors: Massie Allyssa A. , Denler Melissa C. , Cardoso Luísa Thiara , Walker Ashlie N. , Hossain M. Kamal , Day Victor W. , Nordlander Ebbe , Jackson Timothy A.
Published: March 2017

Manganese(IV)‐oxo complexes are often invoked as intermediates in Mn‐catalyzed C−H bond activation reactions. While many synthetic MnIV‐oxo species are mild oxidants, other members of this class can attack strong C−H bonds. The basis for these reactivity differences is not well understood. Here we describe a series of MnIV‐oxo complexes with N5 pentadentate ligands that modulate the equatorial ligand field of the MnIV center, as assessed by electronic absorption, electron paramagnetic resonance, and Mn K‐edge X‐ray absorption methods. Kinetic experiments show dramatic rate variations in hydrogen‐atom and oxygen‐atom transfer reactions, with faster rates corresponding to weaker equatorial ligand fields. For these MnIV‐oxo complexes, the rate enhancements are correlated with both 1) the energy of a low‐lying 4E excited state, which has been postulated to be involved in a two‐state reactivity model, and 2) the MnIII/IV reduction potentials.
Genetic population structure of black‐browed and Campbell albatrosses, and implications for assigning provenance of birds killed in fisheries
Authors: Burg Theresa M. , Catry Paulo , Ryan Peter G. , Phillips Richard A.
Published: March 2017

Previous genetic studies found evidence of at least three distinct groups of black‐browed Thalassarche melanophris and Campbell Thalassarche impavida albatrosses in the Southern Ocean. Almost 350 individuals including samples from additional breeding sites on the Falkland Islands and South Georgia Island were screened using mitochondrial DNA.

The new sequence data using lineage specific PCR primers provided further support for the taxonomic split of T. melanophris and T. impavida and separate management of the two distinct T. melanophris groups.

In total, 207 black‐browed albatrosses killed in longline fisheries were screened. Approximately 93% of the bycaught birds from the Falkland Islands belonged to the Falkland mtDNA group and the remaining birds had mtDNA from the Widespread T. melanophris group; these proportions were similar to those in the local Falklands breeding population. The South African and South Georgia bycatch samples predominantly comprised the Widespread T. melanophris group, with only one bird from each area containing Falkland mtDNA. Lastly, 81% of the albatrosses bycaught off New Zealand had T. impavida mtDNA and the remaining four birds were Widespread T. melanophris. These differences in bycatch composition matched what is known from tracking and banding data about the at‐sea distribution of black‐browed albatrosses.

Based on the mtDNA results and current population trends, consideration should be given to assigning regional IUCN status for the different breeding populations.
Breast cancer and genomic testing
Authors: Liedtke C , Kolberg H-C
Published: March 2017

Makes a real difference
Prehabilitation in perioperative care
Authors: Moorthy K , Wynter-Blyth V
Published: March 2017

More work needed on improving fitness for surgery
The effect of tripterygium glucoside tablet on pharmacokinetics of losartan and its metabolite EXP3174 in rats
Authors: Hu Yongsheng , Zhou Xuexue , Shi Hui , Shi Wenyu , Ye Shengjie , Zhang Hai
Published: March 2017

Losartan and tripterygium glucoside tablet (TGT) are often simultaneously used for reducing urine protein excretion in clinic. However, it is unknown whether there is potential herb–drug interaction between losartan and TGT. The aim of this study was to investigate their potential herb–drug interaction, and clarify the mechanism of the effect of TGT on the pharmacokinetics of losartan and its metabolite EXP3174 in rats. The plasma concentrations of losartan and EXP3174 were determined by LC–MS, and the main pharmacokinetic parameters were calculated. The Cmax, t1/2 and AUC(0–t) of losartan became larger after co‐administration, while the Cmax and AUC(0–t) of EXP3174 became smaller, suggesting that TGT could influence the pharmacokinetics of losartan and EXP3174. The effects of TGT and its main components on the metabolic rate of losartan were further investigated in rat liver microsomes. Results indicated that TGT and its two main ingredients could decrease the metabolic rate of losartan. Therefore, it was speculated that TGT might increase the plasma concentration of losartan and decrease the concentration of EXP3174 by inhibiting the metabolism of losartan. The results could provide references for clinical medication guidance of losartan and TGT to avoid the occurrence of adverse reactions.
Acute stroke alert activation, emergency service use, and reperfusion therapy in Sweden
Authors: Eriksson Marie , Glader Eva‐Lotta , Norrving Bo , Stegmayr Birgitta , Asplund Kjell
Published: March 2017

Objectives

Ambulance services and stroke alerts reduce the time from stroke onset to acute stroke diagnosis. We describe the use of stroke alerts and ambulance services in different hospitals and patient groups and their relationship with reperfusion therapy.

Methods

This nationwide study included 49,907 patients admitted with acute stroke who were registered in The Swedish Stroke Register (Riksstroke) in 2011–2012.

Results

The proportions of patients admitted as stroke alerts out of all acute stroke admissions varied from 12.2% to 45.7% in university hospitals (n = 9), 0.5% to 38.7% in specialized nonuniversity hospitals (n = 22), and 4.2% to 40.3% in community hospitals (n = 41). Younger age, atrial fibrillation (AF), living in an institution, reduced consciousness upon admission, and hemorrhagic stroke were factors associated with a higher probability of stroke alerts. Living alone, primary school education, non‐European origin, previous stroke, diabetes, smoking, and dependency in activities of daily living (ADL) were associated with a lower probability of stroke alert. The proportion of patients arriving at the hospital by ambulance varied from 60.3% to 94.5%. Older age, living alone, primary school education, being born in a European country, previous stroke, AF, dependency in ADL, living in an institution, reduced consciousness upon admission, and hemorrhagic stroke were associated with ambulance services. Hospital stroke alert frequencies correlated strongly with reperfusion rates (r = .75).

Conclusion

Acute stroke alerts have a significant potential to improve stroke reperfusion rates. Prehospital stroke management varies conspicuously between hospitals and patient groups, and the elderly and patients living alone have a markedly reduced likelihood of stroke alerts.
The regulation of tumor‐suppressive microRNA, miR‐126, in chronic lymphocytic leukemia
Authors: Guinn Daphne , Lehman Amy , Fabian Catherine , Yu Lianbo , Maddocks Kami , Andritsos Leslie A. , Jones Jeffrey A. , Flynn Joseph M. , Jaglowski Samantha M. , Woyach Jennifer A. , Byrd John C. , Johnson Amy J.
Published: March 2017

The introduction of miR profiling of chronic lymphocytic leukemia (CLL) patients with different cytogenetic profiles and responses to therapy has allowed incorporation of important miR‐mRNA interactions into the understanding of disease biology. In this study, we performed miR expression analysis using NanoString nCounter to discover differentially regulated miRs after therapy with the Bruton tyrosine kinase inhibitor ibrutinib. Of the differentially regulated miRs in the discovery set, miR‐29c and miR‐126 were confirmed using real‐time PCR to be upregulated in CLL patient cells with ibrutinib therapy. In the validation set, an inverse correlation was observed between miR‐126 levels and expression of its putative target p85β, an isoform of the phosphoinositide 3‐kinase p85 regulatory subunit. We found that mRNA for the host gene EGFL7, primary unprocessed miR‐126, and mature miR‐126 are all downregulated in CLL cells compared to normal B cells. Patients in later stages of disease have a greater decrease in miR‐126 expression compared to treatment‐naive patients, indicating that lower miR‐126 levels may associate with disease progression. Overexpression of miR‐126 in leukemia cell lines significantly downregulates p85β expression and decreases activation of prosurvival mitogen‐activated protein kinase (MAPK) signaling. These results implicate miR‐126 in the pathology of CLL.
Conjugation of a Dipicolyl Chelate to Polypeptide Conjugates Increases Binding Affinities for Human Serum Albumin and Survival Times in Human Serum
Authors: Balliu Aleksandra , Baltzer Lars
Published: March 2017

The affinity for human serum albumin (HSA) of a series of 2–5 kDa peptides covalently linked to 3,5‐bis[[bis(2‐pyridylmethyl)amino]methyl]benzoic acid, a dipicolyl chelator with micromolar affinity for Zn2+, was found by surface plasmon resonance to increase in the presence of 1 μm ZnCl2 at physiological pH. The dependence on polypeptide hydrophobicity was found to be minor, thus suggesting that the conjugates bound to the metal‐binding site and not to the fatty‐acid‐binding site. The affinity of the conjugates increased strongly with the positive charge of the polypeptides, thus implicating the negatively charged protein surface surrounding the metal‐binding site. The survival times of the peptides in human serum were extended as a consequence of stronger binding to HSA, thus suggesting that Zn2+‐chelating agents might provide a general route to increased survival time of peptides in serum in therapeutic and diagnostic applications without significantly increasing their molecular weights.
Acute suppurative thyroiditis in infected thyroid cyst in an adult patient under hemodialysis
Authors: Igarashi Hiroyuki , Yoshino Hiroshi , Hijikata Mai , Kumashiro Naoki , Ando Yasuyo , Uchino Hiroshi , Tsuboi Kumiko , Hirose Takahisa
Published: March 2017

Key Clinical Message

Acute suppurative thyroiditis (AST) accompanied by an abscess is a rare clinical case. Hemodialysis patients are at risk for infections. Sepsis mortality was from 100 to 300 times higher for chronic dialysis patients than that for the general public. Thus, special care should be taken against infection in patients under hemodialysis.
Ibrutinib‐induced severe liver injury
Authors: Nandikolla Amara G. , Derman Olga , Nautsch Deborah , Liu Qiang , Massoumi Hatef , Venugopal Sangeetha , Braunschweig Ira , Janakiram Murali
Published: March 2017

Key Clinical Message

Ibrutinib, an inhibitor of the Bruton's tyrosine kinase of the B‐cell receptor pathway, is an effective therapeutic agent for B‐cell lymphomas. As these drugs are novel, long‐term or rare adverse events are not yet known. We report the first case of ibrutinib‐induced severe liver injury in a patient with relapsed/refractory CLL.
Effects of Tenapanor on Cytochrome P450‐Mediated Drug‐Drug Interactions
Authors: Johansson Susanne , Rosenbaum David P. , Ahlqvist Marie , Rollison Helen , Knutsson Mikael , Stefansson Bergur , Elebring Marie
Published: March 2017

Tenapanor (RDX5791, AZD1722) is an inhibitor of sodium/hydrogen exchanger isoform 3 in development for the treatment of constipation‐predominant irritable bowel syndrome and the treatment of hyperphosphatemia in patients with chronic kidney disease on dialysis. We aimed to investigate whether tenapanor inhibits or induces cytochrome P450s (CYPs). In vitro experiments assessing the potential of tenapanor to affect various CYPs indicated that it could inhibit CYP3A4/5 (IC50 0.4‐0.7 μM). An open‐label, phase 1 clinical study (NCT02140268) evaluated the pharmacokinetics of the CYP3A4 substrate midazolam when administered with and without tenapanor. Healthy volunteers received a single oral dose of midazolam 7.5 mg on day 1 followed by tenapanor 15 mg twice daily on days 2 to 15, with an additional single 7.5‐mg midazolam dose coadministered on day 15. Midazolam exposure was similar whether it was administered alone or with tenapanor (geometric least‐squares mean ratio [90%CI] for [midazolam + tenapanor]/midazolam: area under the concentration‐time curve, 107% [101% to 113%]; Cmax 104% [89.6% to 122%]). Findings were similar for metabolites of midazolam. These results indicate that tenapanor 15 mg twice daily does not have a clinically relevant impact on CYP3A4 in humans and suggest that tenapanor can be coadministered with CYP3A4‐metabolized drugs without affecting their exposure.
Cycloisomerization of Pyridine‐Substituted Propargylic Alcohols or Esters To Construct Indolizines and Indolizinones
Authors: Wang Li‐Xia , Tang Ya‐Lin
Published: March 2017

Nitrogen‐containing heterocycles are found in a vast number of natural products and biologically active compounds, and have attracted a lot of attention. Among all the reported methods, cycloisomerization transformations involving the activation of alkynes with the aid of transition metals are a very active area in synthetic organic chemistry. This review covers the most important recent advances in the use of metal‐catalyzed or metal‐free cycloisomerizations for the preparation of indolizines and indolizinones from starting substrates consisting of pyridine‐containing propargylic esters or alcohols. Cycloisomerization transformations to heterocycles are very efficient and atom‐economic, and we hope that this review will result in further focused research to widen the application of indolizines and indolizinones.
Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders
Authors: Liu Beihui , Teschemacher Anja G. , Kasparov Sergey
Published: March 2017

Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.
Implementing California's Law on Assisted Dying
Authors: Mishra Ruchika
Published: March 2017

On October 5, 2015, Governor Jerry Brown approved bill ABX2 15, the End of Life Option Act, making California the fifth state in the country to allow physician‐assisted dying. The law was modeled after Oregon's 1997 Death with Dignity Act. When the legislative special session ended on March 10, 2016, California health care providers had only ninety days to respond to the state mandate before the law would take effect, on June 9, 2016. Experience with the law so far suggests several challenges with implementation.
Reprioritizing Research Activity for the Post‐Antibiotic Era:Ethical, Legal, and Social Considerations
Authors: Hey Spencer Phillips , Kesselheim Aaron S.
Published: March 2017

Many hold that the so‐called golden era of antibiotic discovery has passed, leaving only a limited clinical pipeline for new antibiotics. A logical conclusion of such arguments is that we need to reform the current system of antibiotic drug research—including clinical trials and regulatory requirements—to spur activity in discovery and development. The United States Congress in the past few years has debated a number of bills to address this crisis, including the 2012 Generating Antibiotic Incentives Now Act and the 2016 21st Century Cures Act. Experts have also sought to advance antibiotic development by encouraging greater use of trials with noninferiority hypotheses, which are thought to be easier to conduct. The goal underlying these proposals is to stave off the post‐antibiotic era by expanding the pharmaceutical armamentarium as quickly as possible. But although new antibiotic agents are necessary to combat the long‐term threat of drug‐resistant disease, we argue that these research policies, which effectively lower the bar for antibiotic approval, are ethically problematic. Rather, given broader public health considerations related to the full lifecycle of antibiotic use—including development of resistance—we should reject an overly permissive approach to new antibiotic approval and instead set the bar for regulatory approval at a point that will naturally direct research resources toward the most transformative chemical or social interventions.
Mother and child narrative elaborations during booksharing in low‐income Mexican‐American dyads
Authors: Escobar Kelly , Melzi Gigliana , Tamis‐LeMonda Catherine S.
Published: March 2017

Caregivers' narrative elaborations have been consistently shown to relate to language, literacy, and cognitive skills in children. However, research with Latinos yields mixed findings in terms of how much caregivers elaborate and the benefits of elaborations for Latino children's development, especially within booksharing contexts. Moreover, little research has investigated whether and how children elaborate, and whether individual differences among children's narrative elaborations are related to changes in maternal elaborations over time. The current longitudinal study describes specific types of elaborations used by children and mothers and examines reciprocal relations between children's and mothers' elaborations over 1 year (at child age 3 and child age 4), in a sample of 45 Mexican immigrant mothers and their preschool‐aged children. Maternal elaborations positively related to children's narrative development only when subtypes of elaborations were considered, but not when considering the frequency of elaborations more broadly. Moreover, children's elaborations at age 3 were differentially associated with specific maternal elaborations a year later. Findings underscore the need to examine narrative elaborations at a nuanced level in Latino populations.

Highlights

This paper examines the specific ways in which Latino dyads elaborate during booksharing interactions

Dyads were video recorded sharing a wordless picture book at two time points over 1 year. Findings suggest that specific elaboration types, namely, dyadic forms of responses and requests, are most important for the development of concurrent narrative skills, even though they are the least frequently used in this context

We conclude that the investigation of narrative elaborations needs to be approached at a more nuanced level when studying Latino populations, as there are various roles taken and behaviors expected when changing the narrative context. These findings have implications for the development of culturally appropriate interventions targeted at enhancing booksharing practices with Latino groups
Can the Hopelessness Model of Depression and Response Style Theory Be Integrated?
Authors: Pössel Patrick , Winkeljohn Black Stephanie
Published: March 2017

The Hopelessness Model (Abramson, Alloy, & Metalsky, ) and response style theory (Nolen‐Hoeksema, Girgus, & Seligman, ) have been integrated in various ways, but these integrations have not been compared. German college students (N = 311, mean age = 23.27 years, SD = 6.57 years, 80% female) rated their depressive symptoms, negative inferences, and rumination 3 times. Findings supported an integrated model whereby individual inferences predict and interact with the rumination subtype brooding to affect depressive symptoms.
A National Survey on Multicultural Competence for Professional Counselors: A Replication Study
Authors: Barden Sejal M. , Sherrell Renee S. , Matthews Jennifer J.
Published: March 2017

The purpose of this investigation was to replicate findings from Holcomb‐McCoy and Myers's () study, which assessed the multicultural competence of professional counselors. Factor analysis was conducted to determine the components of multicultural competence (N = 171). Differences existed between multicultural competence and race/ethnicity, F(2, 168) = 4.86, p = .009, Wilks's Λ = .95, partial η2 = .06, and education level, F(2, 167) = 8.95, p < .001, Wilks's Λ = .82, partial η2 = .10.
Examination of the Stigmas Toward Help Seeking Among Turkish College Students
Authors: Topkaya Nursel , Vogel David L. , Brenner Rachel E.
Published: March 2017

This study builds on previous help‐seeking research in the United States by examining the role of counseling stigma in Turkey. Undergraduate students in Turkey (N = 520) completed self‐report measures of attitudes and intentions to seek counseling and 3 forms of help‐seeking stigma. Results indicated that perceptions of public and social network stigma each uniquely contributed to the experience of self‐stigma, which, in turn, influenced attitudes toward seeking counseling and then help‐seeking intentions.
Complicated Grief: An Evolving Theoretical Landscape
Authors: Crunk A. Elizabeth , Burke Laurie A. , Robinson E. H. Mike
Published: March 2017

The bereavement literature has proliferated in recent decades, generating a shift from conceptualizing grief as a stepwise, uniform process to an idiosyncratic experience that varies among individuals. Among the most notable developments is the empirical exploration of complicated grief—a protracted, debilitating, sometimes life‐threatening response to the death of a loved one—and the testing of novel interventions to treat it. This article provides counselors with recommendations for identifying and treating complicated grief.
Analysis of Stroma Labeling During Multiple Passage of a Sarcoma Imageable Patient‐Derived Orthotopic Xenograft (iPDOX) in Red Fluorescent Protein Transgenic Nude Mice
Authors: Kiyuna Tasuku , Murakami Takashi , Tome Yasunori , Kawaguchi Kei , Igarashi Kentaro , Miyake Kentaro , Kanaya Fuminori , Singh Arun , Eilber Fritz C. , Hoffman Robert M.
Published: March 2017

A patient‐derived orthotopic xenograft (PDOX) model of undifferentiated pleomorphic sarcoma (UPS) was previously established that acquired red fluorescent protein (RFP)‐expressing stroma by growth in an RFP transgenic nude mouse. In the present study, an imageable PDOX model (iPDOX) of UPS was established by orthotopic implantation in the biceps femoris of transgenic RFP nude mice. After the tumors grew to a diameter of 10 mm, they were harvested and the brightest portion of the tumors were subsequently orthotopically transplanted to both RFP and non‐colored nude mice. The UPS PDOX tumor was again transplanted to RFP transgenic and non‐colored nude mice, and finally a 3rd passage was made in the same manner. Five UPS tumors from each passage in both RFP and non‐colored mouse models were harvested. The FV1,000 confocal microscope was used to visualize and quantitate the RFP area of the resected tumors. The average percent fluorescent area in the first passage of RFP mice was 34 ± 22%; in the second passage, 34 ± 20%; and 36 ± 11% in the third passage of RFP transgenic nude mice. The average tumor RFP area in the first passage from RFP mice to non‐colored mice was 20 ± 7%; in the second passage, 28 ± 11%; in the third passage was 27 ± 13%. The present results demonstrate the extensive and stable acquisition of stroma by the UPS‐tumor growing orthotopically in transgenic RFP nude mice (iPDOX). This model can be used for screening for effective drugs for individual patients and drug discovery. J. Cell. Biochem. 118: 3367–3371, 2017. © 2017 Wiley Periodicals, Inc.
Clinical Significance and Prognosis Value of Wnt Signaling Pathway in Cervical Cancer
Authors: Bahrami Afsane , Hasanzadeh Malihe , ShahidSales Soodabeh , Yousefi Zohre , Kadkhodayan Sima , Farazestanian Marjaneh , Joudi Mashhad Mona , Gharib Masoumeh , Mahdi Hassanian Seyed , Avan Amir
Published: March 2017

Cervical cancer is among the most commonly diagnosed cancer in women, supporting the need for identification of novel prognostic and predictive biomarkers to predict the risk of developing of this malignancy or predict the prognosis of patients. Against this background, the activation of the Wingless‐type (Wnt)/β‐catenin pathway has been suggested as the main dysregulated pathways, which is involved in the multistep process of cervical carcinogenesis, suggesting its value as a potential biomarker or therapeutic target. The aim of current review is to give an overview about the potential application of WNT pathway and its value which is differentially expressed in cervical cancer versus non‐tumorigenic tissue as biomarker for risk stratification and predict the prognosis of patients with cervical cancer. J. Cell. Biochem. 118: 3028–3033, 2017. © 2017 Wiley Periodicals, Inc.
Behavior analysis and neuroscience: Complementary disciplines
Authors: Donahoe John W.
Published: March 2017

Behavior analysis and neuroscience are disciplines in their own right but are united in that both are subfields of a common overarching field—biology. What most fundamentally unites these disciplines is a shared commitment to selectionism, the Darwinian mode of explanation. In selectionism, the order and complexity observed in nature are seen as the cumulative products of selection processes acting over time on a population of variants—favoring some and disfavoring others—with the affected variants contributing to the population on which future selections operate. In the case of behavior analysis, the central selection process is selection by reinforcement; in neuroscience it is natural selection. The two selection processes are inter‐related in that selection by reinforcement is itself the product of natural selection. The present paper illustrates the complementary nature of behavior analysis and neuroscience through considering their joint contributions to three central problem areas: reinforcement—including conditioned reinforcement, stimulus control—including equivalence classes, and memory—including reminding and remembering.
Mitochondrial biogenesis in neurodegeneration
Authors: Li P. Andy , Hou Xiaolin , Hao Shaocai
Published: March 2017

Mitochondria play a key role in energy production, calcium homeostasis, cell survival, and death. Adverse stimulations including neurodegenerative diseases may result in mitochondrial dynamic imbalance, free radical production, calcium accumulation, intrinsic cell death pathway activation and eventually cell death. Therefore, preserving or promoting mitochondrial function is a potential therapeutic target for the treatment of neurodegenerative disorders. Mitochondrial biogenesis is a process by which new mitochondria are produced from existing mitochondria. This biogenesis process is regulated by Peroxisome proliferator‐activated receptor‐gamma (PPARγ) coactivator‐1alpha (PGC‐1α). Once being activated by either phosphorylation or de‐acetylation, PGC‐1α activates nuclear respiratory factor 1 and 2 (NRF1 and NRF2), and subsequently mitochondrial transcription factor A (Tfam). The activation of this PGC‐1α ‐ NRF –Tfam pathway leads to synthesis of mitochondrial DNA and proteins and generation of new mitochondria. © 2017 Wiley Periodicals, Inc.
Evaluation of intra‐seasonal oscillation simulations in IPCC AR5 coupled GCMs associated with the Asian summer monsoon
Authors: Hu Wenting , Duan Anmin , He Bian
Published: March 2017

In this study, we systematically evaluate the intra‐seasonal oscillation (ISO) associated with the Asian summer monsoon region in coupled general circulation models (GCMs) participating in the Intergovernmental Panel on Climate Change (IPCC) Fifth Assessment Report (AR5). Results show that most of the models simulate reasonable climatological circulation patterns in boreal summer, but insufficient precipitation over the Bay of Bengal (BOB) and western North Pacific summer monsoon region. Most models underestimate the variance of 12–90‐day ISO mode but overestimate the percent variance of 12–90‐day ISO accounting for raw precipitation anomalies. There remains a wide gap between model simulations and observations in the simulations of eastward‐propagating ISO (30–80‐day), while the models perform better in the northward propagation of the 30–80‐day mode and the westward propagation of the 12–24‐day mode.

In addition, mean state circulation, atmospheric internal dynamic process, air–sea interactions and model resolution have varying degrees of impacts on the ISO simulation. The local Hadley and Walker cell biases are investigated in this study, which might relate well with the precipitation bias in models. Within the similar background of vertical easterly shear, few models have the capacity to simulate the equivalent barotropic vorticity to the north of the convection centre. Furthermore, many models have difficulty in reproducing the strong air–sea interactions over the Indian Ocean and the BOB. Our results indicate that simply improving model resolution is not an effective method to obtain more reasonable propagation characteristics of the ISO, especially for eastward propagation. Therefore, further improving the capacity of the ISO simulation remains a great challenge for future development of climate system models.
Extracellular carbonic anhydrase: Method development and its application to natural seawater
Authors: Mustaffa Nur Ili Hamizah , Striebel Maren , Wurl Oliver
Published: March 2017

We developed an effective fluorometric technique to quantify extracellular carbonic anhydrase (eCA) present in natural seawater samples. The technique includes the separation of eCA from cells to achieve low detection limits through high signal : noise ratios. eCA was efficiently extracted from cell membranes by treatment with 0.1 M phosphate buffer containing 2.5 M NaCl. The free eCA specifically forms a fluorescent complex with dansylamide, and the detection limit of the complex is below 0.1 nM. We applied the technique to samples from different culture solutions and natural seawater collected from the Baltic Sea. We observed eCA concentrations to be in the range of 0.10–0.67 nM in natural seawater. The data indicated that this technique is very sensitive, accurate, and feasible for routine and shipboard measurement of eCA from natural seawater. It is therefore an effective and rapid tool to investigate the carbon acquisition of phytoplankton both in mono culture as well natural communities.