bluuebunny/crossref_metadata_2025 huggingface dataset:
NCCN Task Force Report: Evaluating the Clinical Utility of Tumor Markers in Oncology
Authors: Febbo Phillip G. , Ladanyi Marc , Aldape Kenneth D. , De Marzo Angelo M. , Hammond M. Elizabeth , Hayes Daniel F. , Iafrate A. John , Kelley R. Kate , Marcucci Guido , Ogino Shuji , Pao William , Sgroi Dennis C. , Birkeland Marian L.
Published: April 2017

The molecular analysis of biomarkers in oncology is rapidly advancing, but the incorporation of new molecular tests into clinical practice will require a greater understanding of the genetic changes that drive malignancy, the assays used to measure the resulting phenotypes and genotypes, and the regulatory processes that new molecular biomarkers must face to be accepted for clinical use. To address these issues and provide an overview of current molecular testing in 6 major malignancies, including glioma, breast cancer, colon cancer, lung cancer, prostate cancer, and acute myelogenous leukemia, an NCCN Task Force was convened on the topic of evaluating the clinical utility of tumor markers in oncology. The output of this meeting, contained within this report, describes the ways biomarkers have been developed and used; defines common terminology, including prognostic, predictive, and companion diagnostic markers, and analytic validity, clinical validity, and clinical utility; and proposes the use of a combination level of evidence score to aid in the evaluation of novel biomarker tests as they arise. The current state of regulatory oversight and anticipated changes in the regulation of molecular testing are also addressed.
NCCN Molecular Testing White Paper: Effectiveness, Efficiency, and Reimbursement
Authors: Engstrom Paul F. , Bloom Mara G. , Demetri George Daniel , Febbo Phillip G. , Goeckeler William , Ladanyi Marc , Loy Bryan , Murphy Kate , Nerenberg Michael , Papagni Paul , Robson Mark , Sweetman Robert W. , Tunis Sean , DeMartino Jessica , Larsen Jonathan K.
Published: April 2017

Personalized medicine in oncology is maturing and evolving rapidly, and the use of molecular biomarkers in clinical decision-making is growing. This raises important issues regarding the safe, effective, and efficient deployment of molecular tests to guide appropriate care, specifically regarding laboratory-developed tests and companion diagnostics. In May 2011, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations to identify challenges and provide guidance regarding molecular testing in oncology and its corresponding utility from clinical, scientific, and coverage policy standpoints. The NCCN Molecular Testing Work Group identified challenges surrounding molecular testing, including health care provider knowledge, determining clinical utility, coding and billing for molecular tests, maintaining clinical and analytic validity of molecular tests, efficient use of specimens, and building clinical evidence.
Neoadjuvant Imatinib for Borderline Resectable GIST
Authors: Koontz M. Zach , Visser Brendan M. , Kunz Pamela L.
Published: April 2017

A 36-year-old woman presented to the emergency department with black stools and syncope. Her hemoglobin was 7.0 and her red blood cells were microcytic. Upper endoscopy did not identify a clear source of bleeding, but a bulge in the third portion of the duodenum was noted. A CT scan showed a large extraintestinal mass, and follow-up esophagogastroduodenoscopy/endoscopic ultrasound with biopsy revealed a spindle cell neoplasm, consistent with gastrointestinal stromal tumor (GIST). Because of the size of the lesion and association with the superior mesenteric vein and common bile duct, she was referred to medical oncology for consideration of neoadjuvant imatinib. Neoadjuvant tyrosine kinase inhibitor therapy for GISTs is emerging as a viable treatment strategy for borderline resectable tumors, although the dose, duration, and optimal imaging modalities have not been clearly established. Recent pathologic and radiographic data have provided insight into the mechanism and kinetics of this approach. This case report presents a patient for whom surgery was facilitated using neoadjuvant imatinib.
Strategies for Optimizing the Clinical Impact of Immunotherapeutic Agents Such as Sipuleucel-T in Prostate Cancer
Authors: Madan Ravi A. , Schwaab Thomas , Gulley James L.
Published: April 2017

Sipuleucel-T is a therapeutic cancer vaccine that has shown improved survival in men with metastatic castration-resistant prostate cancer. As a first-in-class agent, it has been met with both fan-fare and controversy. A broad review of immune-based therapies may reveal the delayed clinical impact of sipuleucel-T to be a class effect. As new strategies of immune-based therapy are developed, their effects can be optimized through better understanding of how they affect disease differently from more standard therapeutics. Furthermore, combination therapy with agents that can either work synergistically with immune-activating therapies or deplete immune-regulating cells may result in more vigorous immune responses and improved clinical outcomes. In addition, therapeutic vaccines may be ideal candidates to safely combine with standard-of-care therapies because of their nonoverlapping toxicity profile. The ultimate role of immunotherapy may not be to supplant standard therapies, but rather to work in concert with them to maximize clinical benefit for patients.
Rectal Cancer
Authors: Benson Al B. , Bekaii-Saab Tanios , Chan Emily , Chen Yi-Jen , Choti Michael A. , Cooper Harry S. , Engstrom Paul F. , Enzinger Peter C. , Fakih Marwan G. , Fuchs Charles S. , Grem Jean L. , Hunt Steven , Leong Lucille A. , Lin Edward , Martin Michael G. , May Kilian Salerno , Mulcahy Mary F. , Murphy Kate , Rohren Eric , Ryan David P. , Saltz Leonard , Sharma Sunil , Shibata David , Skibber John M. , Small William , Sofocleous Constantinos T. , Venook Alan P. , Willett Christopher G. , Freedman-Cass Deborah A. , Gregory Kristina M.
Published: April 2017

These NCCN Clinical Practice Guidelines in Oncology provide recommendations for the management of rectal cancer, beginning with the clinical presentation of the patient to the primary care physician or gastroenterologist through diagnosis, pathologic staging, neoadjuvant treatment, surgical management, adjuvant treatment, surveillance, management of recurrent and metastatic disease, and survivorship. This discussion focuses on localized disease. The NCCN Rectal Cancer Panel believes that a multidisciplinary approach, including representation from gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology, is necessary for treating patients with rectal cancer.
Equity in Cancer Care: Pathways, Protocols, and Guidelines
Authors: DeMartino Jessica K. , Larsen Jonathan K.
Published: April 2017

The quality of patient care varies based on numerous factors, such as health care setting, geographic location, access to medications, insurance coverage, and treatment protocols. Recently, the issue of whether use of clinical pathways can reduce costs and inappropriate variability in care has been the subject of much debate. As clinical treatment guidelines and pathways are increasingly deployed in oncology practice, they have a growing impact on the quality of treatment and how it is delivered. To fulfill the current need to discuss the use of pathways and clinical treatment guidelines in oncology and to address how patient care is impacted by their use, the National Comprehensive Cancer Network convened the NCCN Oncology Policy Summit: Equity in Cancer Care–Pathways, Protocols, and Guidelines. The summit was a forum to discuss the use and implementation of pathways, including how much flexibility pathways should allow in care, pathways’ impact on public and private health insurance benefit design, what data is used to select pathway regimens and protocols, and ultimately what impact pathways may have on variation in care. The use and implementation of clinical treatment guidelines in practice was also explored from a variety of perspectives.
Photodynamic Therapy for Pancreatic and Biliary Tract Cancer: The United Kingdom Experience
Authors: Pereira Stephen
Published: April 2017

Pancreaticobiliary cancer remains a challenging cancer to treat, with a small group of patients having resectable disease and few long-term survivors. Stenting remains the treatment of choice for biliary obstruction, but optimal stenting is difficult. Resection and chemoradiotherapy are indicated for localized pancreatic cancer, and gemcitabine-based chemotherapy may be considered the standard of care for advanced/metastatic pancreatic disease. In the search for better therapeutic alternatives, the role of photodynamic therapy (PDT) for both pancreatic and biliary tract cancers has been evaluated. Although conflicting and often poor-quality data have emerged on the use of PDT for unresectable bile duct cancers and encouraging early-stage studies with PDT are under way for unresectable, locally advanced pancreatic cancer, definitive answers as to its efficacy can only be found in randomized controlled trials.
Photodynamic Therapy for Malignant Pleural Mesothelioma
Authors: Friedberg Joseph S.
Published: April 2017

Surgery is the treatment option most likely to be associated with prolonged remission in patients with malignant pleural mesothelioma. However, it remains investigational and must always be combined with other modalities to treat the microscopic disease that remains after the most aggressive operations. Improvements in quality of life for appropriate patients with this rare yet incurable cancer may be obtained with less drastic lung-sparing surgical procedures along with intraoperative use of photodynamic therapy (PDT). Very encouraging survival results have been obtained with the combination of surgery and PDT, which requires the well-orchestrated collaborative effort of an extensive team of professionals, from thoracic surgeons and radiation oncologists to basic science researchers. Multi-institutional trials are necessary to duplicate these early findings and shed more light on the tumor-directed immune response of this surgically based multimodal treatment.
The Affordable Care Act: Where Are We Now? An NCCN Roundtable
Authors: Downs Christian G. , Fowler Liz , Kolodziej Michael , Newcomer Lee H. , Ogaily Mohammed S. , Purcell W. Thomas , Winkelmann John C. , Goodman Clifford
Published: April 2017

The Affordable Care Act (ACA) is a transformational event for health care in the United States, with multiple impacts on health care, the economy, and society. Oncologists and other health care providers are already experiencing many changes—direct and indirect, anticipated and unanticipated. A distinguished and diverse panel assembled at the NCCN 19th Annual Conference to discuss the early phase of implementation of the ACA. The roundtable touched on early successes and stumbling blocks; the impact of the ACA on contemporary oncology practice and the new risk pool facing providers, payers, and patients; and some of the current and future challenges that lie ahead for all.
Treatment of Metastatic Breast Cancer
Authors: Gradishar William J.
Published: April 2017

Many newer agents in combination are being studied in the front-line treatment of women with HER2-positive metastatic breast cancer (MBC), but the story in the endocrine arena is more about the wise use of new strategies to overcome endocrine resistance, because no new antihormonal agents have been approved in the past decade. During his presentation at the NCCN 19th Annual Conference, Dr. William Gradishar explored what’s new in the treatment of MBC, focusing primarily on enhancing the effect of endocrine therapy to overcome resistance with newer targeted agents such as everolimus, reevaluating the role of rebiopsy on disease progression and measuring circulating tumor cells as a surrogate of response to treatment, and reviewing the effective treatment regimens for HER2-positive disease.
NCCN Roundtable: Talking to Children About Cancer
Authors: Aschenbrenner Martha , Ham Bruce , Rauch Paula K. , Sambolin Zoraida , Silver Maya , Shockney Lillie D.
Published: April 2017

A roundtable presentation at the NCCN 19th Annual Conference focused on the child’s experience when a parent has cancer and concluded that honest communication, appropriate to the child’s age and temperament, is essential, and that oncology providers should institute programs that help families deal with the illness.
Chronic Lymphocytic Leukemia: State of the Art and Beyond
Authors: Byrd John C.
Published: April 2017

In the treatment of chronic lymphocytic leukemia (CLL), select genomic studies can assist in risk stratification of newly diagnosed patients. Chemoimmunotherapy targeting CD20 offers a survival advantage in symptomatic patients both with and without these high-risk genetic features, though patients with del(17p13.1) have poor outcomes and require specific intervention. Obinutuzumab plus chlorambucil is a treatment standard for untreated elderly patients and is superior to rituximab plus chlorambucil. In the setting of relapsed CLL, the new kinase inhibitors have the potential to completely change the treatment paradigm of CLL.
Multiple Myeloma: Advances Reported in 2013 Are Useful in the Clinic
Authors: Anderson Kenneth
Published: April 2017

Studies on multiple myeloma reported in 2013 offer support for maintenance after induction and consolidation in newly diagnosed patients eligible for transplantation and for continued lenalidomide in patients not eligible for transplantation. The newest available agents, carfilzomib and pomalidomide, are approved to treat relapsed/refractory myeloma, and in combination they produce impressive response rates and durability. On the horizon, new classes of agents promise even more impressive gains in remission and survival.
NCCN Bone Health Task Force: Key Recommendations
Authors: Farooki Azeez
Published: April 2017

For patients with advanced cancers involving bone, the standard of care for maintaining bone health is the use of antiresorptive therapies such as bisphosphonates, selective estrogen-receptor modulators, and denosumab. However, although long-term adverse events are rare and the risk-benefit ratio of these agents is usually markedly in favor of treatment, clinicians should be aware that they can occur. At the NCCN 19th Annual Conference, Dr. Azeez Farooki presented the key findings of the NCCN Bone Health Task Force, focusing on such topics as screening for osteoporosis; the controversial use of drug holidays from chronic bisphosphonate therapy; the provocative yet unclear story surrounding the potential anticancer benefits of antiresorptive agents; imaging for metastatic bone disease; and safety considerations linked to calcium supplements, vitamin D, and bone-strengthening agents.
Monitoring Molecular Response to Tyrosine Kinase Therapy in Chronic Myelogenous Leukemia
Authors: Radich Jerald P.
Published: April 2017

The dramatic decline in mortality rates in chronic myelogenous leukemia (CML) is a direct result of the advent of tyrosine kinase inhibitors (TKIs) and the dawning of the targeted era. Although many patients experience long-term benefits from imatinib or related agents, problems with resistance and tolerance dampen the outcomes for many others. During his presentation at the NCCN 19th Annual Conference, Dr. Jerald Radich reviewed the ever-expanding menu of TKIs for CML and shared his thoughts on resolving the clinical questions regarding when to start which drugs, how to sequence the drugs, and how best to decide when to change the therapeutic tack.
Treatment Strategies for Myeloid Growth Factors and Intravenous Iron: When, What, and How?
Authors: Crawford Jeffrey , Rodgers George M.
Published: April 2017

Myeloid growth factors can reduce the risk of chemotherapy-induced neutropenia (CIN) and thus impact the survival of patients with cancer. Patients should be assessed for risk, taking into consideration patient-related risk factors and chemotherapy regimens. Patients stratified as having at least a 20% risk for CIN should be considered for prophylactic growth factors. The NCCN Guidelines for Myeloid Growth Factors provide category 1 recommendations for the daily use of filgrastim, tbo-filgrastim, and pegfilgrastim. Cancer-related anemia can be treated with erythropoiesis-stimulating agents, red blood cell transfusion, or intravenous iron.
NCCN Increases the Emphasis on Genetic/Familial High-Risk Assessment in Colorectal Cancer
Authors: Hampel Heather
Published: April 2017

NCCN has developed new guidelines for the assessment of high-risk familial/genetic colorectal cancer, and has positioned these recommendations within the guidelines for detection, prevention, and risk reduction. The Panel recommends that all patients with colorectal cancer be screened for Lynch syndrome, which occurs in 1 of every 35 patients and is the most common form of hereditary colorectal cancer. Such screening could be universal so that all tumors are genetically tested, or screening could be restricted to patients under the age of 70 and those aged 70 and older who meet clinical criteria.
Don’t Neglect Cultural Diversity in Oncology Care
Authors: Muñoz-Antonia Teresita
Published: April 2017

The growing Hispanic population in the United States mandates the need for oncology providers to become more familiar with disease patterns and cultural belief systems that can impact cancer care. “Culturally competent care” should be the mandate of all providers. This comprises awareness of cultural differences, communication in a manner that the patient understands, and respect.
Prevalência e Perfil de mulheres grávidas que sofreram violência física Prevalence and profile of pregnant women who suffered physical violence
Authors: Santos Siellen Mayane Almeida Barreto , Oliveira Zulmerinda Meira , Coqueiro Raildo da Silva , Santos Vanessa Cruz , Anjos Karla Ferraz dos , Casotti Cezar Augusto
Published: April 2017

Objetivo: identificar a prevalência e o perfil de mulheres grávidas vítimas de violência física. Métodos: estudo epidemiológico, descritivo, do tipo seccional, realizado com 105 gestantes acompanhadas em quatro Unidades de Saúde da Família do município de Jequié/BA. A coleta de dados ocorreu por meio dos questionários de Abuse Assessment Screen (AAS), Tolerance, Annoyed, Cut down e Eyeopener (T-ACE) e sociodemográfico, sendo analisados no programa SPSS 15.0. Resultados: a prevalência de mulheres grávidas que sofreram violência física foi de 2,9%. Essas tinham de 21 a 26 anos de idade, cor de pele não branca e sofreram agressões na cabeça, membro superior e troco; a maioria vivia com companheiro que usava álcool. Conclusão: a prevalência e perfil das gestantes vitimas de violência poderá contribuir para implantação/implementação de ações de promoção à saúde da mulher, assim como prevenção e intervenção desse tipo de violência, o que contribuirá ao menos para reduzir esse problema. Descritores: Atenção Primaria à Saúde; mulheres grávidas; saúde da mulher; violência.
Qualidade de vida de mulheres mastectomizadas matriculadas em um programa de reabilitação Quality of life of mastectomized women enrolled in a rehabilitation program
Authors: Galdino Aaderson Rodrigues , Pereira Larissa Dell' Antônio , Costa Neto Sebastião Benício , Brandão-Souza Camila , Amorim Maria Helena Costa
Published: April 2017

Objetivo: Avaliar a qualidade de vida em mulheres matriculadas mastectomizadas em um programa de reabilitação, segundo as variáveis sociodemográficas e clínicas. Metodologia: Trata-se de um estudo descritivo, realizado no Programa de Reabilitação para Mulheres Mastectomizadas, no Espírito Santo, Brasil. A amostra foi composta por 53 mulheres entrevistadas através da Escala Análogo-Visual de Qualidade de Vida de Portadores de Cânceres de Cabeça e Pescoço, adaptada para Portadores de Câncer de Mama com aquiescência dos autores. Os dados obtidos receberam tratamento estatístico no programa SPSS versão 17.0 e as variáveis sociodemográficas foram avaliadas através do coeficiente de correlação de Pearson. Resultados: Identificou-se que mulheres mais jovens, sem reconstrução da mama, casadas e em tratamento de quimioterapia ou hormonioterapia apresentaram maiores perdas da qualidade de vida. Conclusão: Diante disso, destaca-se a importância de intervenções que promovam melhor qualidade de vida a essas pacientes, com atuação interdisciplinar eficaz por parte da equipe de saúde.
Enfermeiro do trabalho na prevenção da silicose: uma revisão integrativa Occupational health nurse in the prevention of silicosis: an integrative review
Authors: Soares Duarte Severina Silvana , Sousa Eliane Leite , Brito Edva Duarte , Xavier de Abreu Rogéria Mônica Seixas , Moreira Maria Rosilene Cândido
Published: April 2017

Objetivo: Averiguar a divulgação do conhecimento sobre silicose e identificar ações do enfermeiro do trabalho para sua prevenção. Método: Trata-se de uma revisão integrativa da literatura realizada nas bases de dados LILACS, SciELO, BDENF e PubMed, utilizando-se os descritores “silicose”, “enfermagem do trabalho” e “pneumoconiose”, nos idiomas português, inglês e espanhol, dos anos de 2004 a 2014. Foram selecionados oito artigos que atenderam aos critérios de inclusão e responderam as questões norteadoras. Resultados: os artigos selecionados abordam a silicose, estimar sua prevalência, delinear o perfil dos portadores, descrever os principais sintomas, identificar fatores de risco associados e avaliar a qualidade de vida dos acometidos. Conclusão: A silicose é um problema de saúde pública com alta prevalência, que necessita de estratégias especificas para seu controle e prevenção, especialmente aquelas desenvolvidas no âmbito da enfermagem do trabalho. Descritores: Silicose, Enfermagem do trabalho, Pneumoconiose.
Organization of tropical convection in low vertical wind shears: Role of updraft entrainment
Authors: Tompkins Adrian M. , Semie Addisu G.
Published: April 2017

Radiative‐convective equilibrium simulations with a 2 km horizontal resolution are conducted to investigate the impact on convective organization of different parameterizations for horizontal and vertical subgrid turbulence mixing. Three standard approaches for representing horizontal diffusion produce starkly differing mixing rates, particularly for the entrainment mixing into updrafts, which differ by more than an order of magnitude between the schemes. The simulations demonstrate that the horizontal subgrid mixing of water vapor is key, with high mixing rates a necessary condition for organization of convection to occur, since entrainment of dry air into updrafts suppresses convection. It is argued that diabatic budgets, while demonstrating the role of spatially heterogeneous radiative heating rates in driving organization, can overlook the role of physical processes such as updraft entrainment. These results may partially explain previous studies that showed that organization is more likely to occur at coarser resolutions, when entrainment is solely represented by subgrid‐scale turbulence schemes, highlighting the need for benchmark simulations of higher horizontal resolution. The recommendation is for the use of larger ensembles to ensure robustness of conclusions to subgrid‐scale parameterization assumptions when numerically investigating convective organization, possibly through a coordinated community model intercomparison effort.
Instability of the Antarctic Ross Sea Embayment as climate warms
Authors: Hughes Terence , Zhao Zihong , Hintz Raymond , Fastook James
Published: April 2017

Collapse of the Antarctic Ice Sheet since the Last Glacial Maximum 18,000 years ago is most pronounced in the Ross Sea Embayment, which is partly ice‐free during Antarctic summers, thereby breaching the O‐ring of ice shelves and sea ice surrounding Antarctica that stabilizes the ice sheet. The O‐ring may have vanished during Early Holocene (5000 to 3000 B.C.), Roman (1 to 400 A.D.), and Medieval (900 to 1300 A.D.) warm periods and reappeared during the Little Ice Age (1300 to 1900 A.D.). We postulate further collapse in the embayment during the post‐1900 warming may be forestalled because East Antarctic outlet glaciers “nail” the Ross Ice Shelf to the Transantarctic Mountains so it can resist the push from West Antarctic ice streams. Our hypothesis is examined for Byrd Glacier and a static ice shelf using three modeling experiments having plastic, viscous, and viscoplastic solutions as more data and improved modeling became available. Observed crevasse patterns were not reproduced. A new research study is needed to model a dynamic Ross Ice Shelf with all its feeder ice streams, outlet glaciers, and ice calving dynamics in three dimensions over time to fully test our hypothesis. The required model must allow accelerated calving if further warming melts sea ice and discerps the ice shelf. Calving must then successively pull the outlet glacier “nails” so collapse of the marine West Antarctic Ice Sheet proceeds to completion.
New insights into Phanerozoic tectonics of South China: Early Paleozoic sinistral and Triassic dextral transpression in the east Wuyishan and Chencai domains, NE Cathaysia
Authors: Li Jianhua , Zhang Yueqiao , Zhao Guochun , Johnston Stephen T. , Dong Shuwen , Koppers Anthony , Miggins Daniel P. , Sun Hanshen , Wang Wenbao , Xin Yujia
Published: April 2017

The northeast Cathaysia area is characterized by an archetypical, transpressional system with widespread strike‐slip shear zones whose geometries, kinematics, and ages are critical for deciphering the Phanerozoic tectonic evolution of South China. We present new structural, geochronological and thermochronological data from the shear zones in the east Wuyishan and Chencai domains, which record two phases of deformation. The first phase corresponds to sinistral oblique shearing along arrays of NNE oriented, steep‐dipping zones under amphibolite facies conditions. The sinistral oblique shearing commenced at ~451 Ma, concurrently with regional NW/SE directed thrust shearing and folding; the coexistence of sinistral and thrust structures indicates NW‐SE transpressive shortening deformation. Dating by40Ar/39Ar shows that such deformation terminated before 400 Ma and was followed by cooling through ~450–350°C at ~400–370 Ma. Our results, merged with published data, aid in tracing an Early Paleozoic orogen that extends through the Jiangnan domain into the northeast Cathaysia, with the southeast Yangtze acting as a foreland belt. The synorogenic shortening was interpreted as resulting from underthrusting of the Cathaysia beneath the east Yangtze. The second phase involved dextral oblique shearing associated with NNE‐SSW transpression under greenschist to amphibolite facies conditions at 245–228 Ma, which was followed by postkinematic magmatism and cooling at ~221–200 Ma. In the Cathaysia, similar Middle Triassic dextral shear zones were widespread and operated with approximately east striking thrusts as mutually complementary structures; their kinematic coupling can be explained by a contractional termination model. Geodynamically, we attributed Middle Triassic dextral transpression to the collisions of South China with North China and Indochina.
Uncertainties related to the representation of momentum transport in shallow convection
Authors: Schlemmer L. , Bechtold P. , Sandu I. , Ahlgrimm M.
Published: April 2017

Convective momentum transport (CMT) has mostly been studied for deep convection, whereas little is known about its characteristics and importance in shallow convection. In this study, CMT by shallow convection is investigated by analyzing both data from large‐eddy simulations (LESs) and reforecasts performed with the Integrated Forecasting System (IFS) of the European Centre for Medium‐Range Weather Forecasts (ECMWF). In addition, the central terms underlying the bulk mass‐flux parametrization of CMT are evaluated offline. Further, the uncertainties related to the representation of CMT are explored by running the stochastically perturbed parametrizations (SPP) approach of the IFS. The analyzed cases exhibit shallow convective clouds developing within considerable low‐level wind shear. Analysis of the momentum fluxes in the LES data reveals significant momentum transport by the convection in both cases, which is directed downgradient despite substantial organization of the cloud field. A detailed inspection of the convection parametrization reveals a very good representation of the entrainment and detrainment rates and an appropriate representation of the convective mass and momentum fluxes. To determine the correct values of mass‐flux and in‐cloud momentum at the cloud base in the parametrization yet remains challenging. The spread in convection‐related quantities generated by the SPP is reasonable and addresses many of the identified uncertainties.
Detrital zircons from the Nanaimo basin, Vancouver Island, British Columbia: An independent test of Late Cretaceous to Cenozoic northward translation
Authors: Matthews W. A. , Guest B. , Coutts D. , Bain H. , Hubbard S.
Published: April 2017

The development of the Cordilleran orogen of western North American is disputed despite a century of study. Paleomagnetic observations require large‐scale dextral displacements of crustal fragments along the western margin of North America, from low latitudes to moderate latitudes during the Cretaceous‐Paleogene. A lack of corroborating geological evidence for large‐scale (>1500 km) displacements has prevented the widespread integration of paleomagnetic data into most contemporary tectonic models for the margin. Here we use detrital zircons from the Nanaimo basin, southwestern British Columbia, Canada as an independent test of its Late Cretaceous paleogeographic position. We compare 4310 detrital zircon U/Pb dates from 16 samples to potential source areas in western North America to test hypothesized northern and southern Late Cretaceous paleogeographic positions. Our detrital zircon data suggest that sediment in the Nanaimo basin derives from either a geographically restricted portion of the Belt‐Purcell basin or the Mojave‐Sonoran region of southwestern North America. A paleogeographic position for the basin adjacent to the Mojave‐Sonoran region is preferred as it is consistent with the paleomagnetic results, but further geological, isotopic, or geophysical data are required to rule out a Belt‐Purcell source.
Iridium‐Catalyzed Intramolecular C–H Silylation of Siloxane‐Tethered Arene and Hydrosilane: Facile and Catalytic Synthesis of Cyclic Siloxanes
Authors: Lin Yan , Jiang Ke‐Zhi , Cao Jian , Zheng Zhan‐Jiang , Xu Zheng , Cui Yu‐Ming , Xu Li‐Wen
Published: April 2017

Catalytic C–H silylation is an increasingly important topic in the field of organosilicon chemistry and homogenous catalysis as well as organic synthesis, but such syntheses and transformations are usually challenging and often incompatible with some functional groups. In this manuscript, a new type of silanol‐directed intramolecular dehydrogenative silylation under iridium catalysis has been developed. The described silylative cyclization has good functional group compatibility, providing a general and efficient route to unsymmetrical cyclic siloxanes with multiple potentially modifiable silicon atoms in high site‐selectivities. The resulting organosilicon compounds exhibit diverse synthetic applications owing to their unique structures.

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A comparative genomic hybridization approach to study gene copy number variations among chinese hamster cell lines
Authors: Vishwanathan Nandita , Bandyopadhyay Arpan , Fu Hsu‐Yuan , Johnson Kathryn C. , Springer Nathan M. , Hu Wei‐Shou
Published: April 2017

Chinese Hamster Ovary (CHO) cells are aneuploid in nature. The genome of recombinant protein producing CHO cell lines continuously undergoes changes in its structure and organization. We analyzed nine cell lines, including parental cell lines, using a comparative genomic hybridization (CGH) array focused on gene‐containing regions. The comparison of CGH with copy‐number estimates from sequencing data showed good correlation. Hierarchical clustering of the gene copy number variation data from CGH data revealed the lineage relationships between the cell lines. On analyzing the clones of a clonal population, some regions with altered genomic copy number status were identified indicating genomic changes during passaging. A CGH array is thus an effective tool in quantifying genomic alterations in industrial cell lines and can provide insights into the changes in the genomic structure during cell line derivation and long term culture. Biotechnol. Bioeng. 2017;114: 1903–1908. © 2017 Wiley Periodicals, Inc.
Non‐hazardous biocatalytic oxidation in Nylon‐9 monomer synthesis on a 40 g scale with efficient downstream processing
Authors: Milker Sofia , Fink Michael J. , Rudroff Florian , Mihovilovic Marko D.
Published: April 2017

This paper describes the development of a biocatalytic process on the multi‐dozen gram scale for the synthesis of a precursor to Nylon‐9, a specialty polyamide. Such materials are growing in demand, but their corresponding monomers are often difficult to synthesize, giving rise to biocatalytic approaches. Here, we implemented cyclopentadecanone monooxygenase as an Escherichia coli whole‐cell biocatalyst in a defined medium, together with a substrate feeding–product removal concept, and an optimized downstream processing (DSP). A previously described hazardous peracid‐mediated oxidation was thus replaced with a safe and scalable protocol, using aerial oxygen as oxidant, and water as reaction solvent. The engineered process converted 42 g (0.28 mol) starting material ketone to the corresponding lactone with an isolated yield of 70% (33 g), after highly efficient DSP with 95% recovery of the converted material, translating to a volumetric yield of 8 g pure product per liter. Biotechnol. Bioeng. 2017;114: 1670–1678. © 2017 Wiley Periodicals, Inc.
Identification and control of novel growth inhibitors in fed‐batch cultures of Chinese hamster ovary cells
Authors: Mulukutla Bhanu Chandra , Kale Jaitashree , Kalomeris Taylor , Jacobs Michaela , Hiller Gregory W.
Published: April 2017

Chinese hamster ovary (CHO) cells in culture are known to consume large amounts of nutrients and divert most of them toward byproducts, some of which, including lactate and ammonia, are known to be toxic in nature. Glucose limitation strategies can successfully control lactate accumulation in fed‐batch cultures yielding higher peak cell densities and titers. Interestingly, even in such optimized cultures, cell growth slows and eventually stops, indicating the emergence of other factors that negatively affect cell growth. In this study, we employed omics techniques to identify and quantify nine compounds that are intermediates or byproducts of amino acid metabolism, and accumulate in fed‐batch cultures. Treatment with these compounds either individually or in a combined fashion resulted in partial or complete cell growth inhibition. Careful control of selected amino acid concentrations between one‐half and one millimolar during the growth phase of fed‐batch cultures reduced accumulation of the inhibitory metabolites and allowed for higher peak cell densities and increased productivity. Biotechnol. Bioeng. 2017;114: 1779–1790. © 2017 Wiley Periodicals, Inc.
An in vitro synthetic biology platform for the industrial biomanufacturing of myo‐inositol from starch
Authors: You Chun , Shi Ting , Li Yunjie , Han Pingping , Zhou Xigui , Zhang Yi‐Heng Percival
Published: April 2017

Myo‐Inositol (vitamin B8) is widely used in the drug, cosmetic, and food & feed industries. Here, we present an in vitro non‐fermentative enzymatic pathway that converts starch to inositol in one vessel. This in vitro pathway is comprised of four enzymes that operate without ATP or NAD+ supplementation. All enzyme BioBricks are carefully selected from hyperthermophilic microorganisms, that is, alpha‐glucan phosphorylase from Thermotoga maritima, phosphoglucomutase from Thermococcus kodakarensis, inositol 1‐phosphate synthase from Archaeoglobus fulgidus, and inositol monophosphatase from T. maritima. They were expressed efficiently in high‐density fermentation of Escherichia coli BL21(DE3) and easily purified by heat treatment. The four‐enzyme pathway supplemented with two other hyperthermophilic enzymes (i.e., 4‐α‐glucanotransferase from Thermococcus litoralis and isoamylase from Sulfolobus tokodaii) converts branched or linear starch to inositol, accomplishing a very high product yield of 98.9 ± 1.8% wt./wt. This in vitro (aeration‐free) biomanufacturing has been successfully operated on 20,000‐L reactors. Less costly inositol would be widely added in heath food, low‐end soft drink, and animal feed, and may be converted to other value‐added biochemicals (e.g., glucarate). This biochemical is the first product manufactured by the in vitro synthetic biology platform on an industrial scale. Biotechnol. Bioeng. 2017;114: 1855–1864. © 2017 Wiley Periodicals, Inc.
Modulation and modeling of monoclonal antibody N‐linked glycosylation in mammalian cell perfusion reactors
Authors: Karst Daniel J. , Scibona Ernesto , Serra Elisa , Bielser Jean‐Marc , Souquet Jonathan , Stettler Matthieu , Broly Hervé , Soos Miroslav , Morbidelli Massimo , Villiger Thomas K.
Published: April 2017

Mammalian cell perfusion cultures are gaining renewed interest as an alternative to traditional fed‐batch processes for the production of therapeutic proteins, such as monoclonal antibodies (mAb). The steady state operation at high viable cell density allows the continuous delivery of antibody product with increased space‐time yield and reduced in‐process variability of critical product quality attributes (CQA). In particular, the production of a confined mAb N‐linked glycosylation pattern has the potential to increase therapeutic efficacy and bioactivity. In this study, we show that accurate control of flow rates, media composition and cell density of a Chinese hamster ovary (CHO) cell perfusion bioreactor allowed the production of a constant glycosylation profile for over 20 days. Steady state was reached after an initial transition phase of 6 days required for the stabilization of extra‐ and intracellular processes. The possibility to modulate the glycosylation profile was further investigated in a Design of Experiment (DoE), at different viable cell density and media supplement concentrations. This strategy was implemented in a sequential screening approach, where various steady states were achieved sequentially during one culture. It was found that, whereas high ammonia levels reached at high viable cell densities (VCD) values inhibited the processing to complex glycan structures, the supplementation of either galactose, or manganese as well as their synergy significantly increased the proportion of complex forms. The obtained experimental data set was used to compare the reliability of a statistical response surface model (RSM) to a mechanistic model of N‐linked glycosylation. The latter outperformed the response surface predictions with respect to its capability and reliability in predicting the system behavior (i.e., glycosylation pattern) outside the experimental space covered by the DoE design used for the model parameter estimation. Therefore, we can conclude that the modulation of glycosylation in a sequential steady state approach in combination with mechanistic model represents an efficient and rational strategy to develop continuous processes with desired N‐linked glycosylation patterns. Biotechnol. Bioeng. 2017;114: 1978–1990. © 2017 Wiley Periodicals, Inc.
Development of Tetramethylenedisulfotetramine (TETS) Hapten Library: Synthesis, Electrophysiological Studies, and Immune Response in Rabbits.
Authors: Barnych Bogdan , Vasylieva Natalia , Joseph Tom , Hulsizer Susan , Nguyen Hai M. , Cajka Tomas , Pessah Isaac , Wulff Heike , Gee Shirley J. , Hammock Bruce D.
Published: April 2017

There is a need for fast detection methods for the banned rodenticide tetramethylenedisulfotetramine (TETS), a highly potent blocker of the γ‐aminobutyric acid (GABAA) receptors. General synthetic approach toward two groups of analogues was developed. Screening of the resulting library of compounds by FLIPR or whole‐cell voltage‐clamp revealed that, despite the structural differences, some of the TETS analogues retained GABAA receptor inhibition; however, their potency was an order of magnitude lower. Antibodies raised in rabbits against some of the TETS analogues conjugated to protein recognized free TETS and will be used for the development of an immunoassay for TETS.
Synthesis and Properties of Salicylaldehydes Fine‐Tuned by Modular Assembly using “Plug‐and‐Socket”‐Type Extendibility
Authors: Houjou Hirohiko , Suzuki Yoshikazu , Shen Qian‐Wen , Yoshikawa Isao , Mutai Toshiki
Published: April 2017

A salicylaldehyde derivative bearing four pyridine arms, 3,5‐bis(N,N‐bis(2‐pyridylmethyl)aminomethyl)‐2,4‐dihydroxybenzaldehyde (Hbpsal) as a “socket”, was prepared and used to derive a series of zinc complexes with various extra anions “plugged” into their vacant site. The crystal structure and 1H NMR spectra were noticeably influenced by the extra anions, allowing fine‐tuning of the properties by “plug‐and‐socket”‐type modification. Similar to unsubstituted salicylaldehyde, the zinc complexes reacted with primary amines to afford Schiff‐base compounds. Because of the potential chirality around the coordination sphere, reaction with a chiral amine resulted in an equilibrium system between diastereomers, the potential of which as chiral sources tunable by the extra anions is discussed. Some of the complexes were further converted into zinc‐ or nickel‐salphen (=N,N‐bis(salicylidene)‐1,2‐phenylenediamine) complexes. The electrochemical properties of the nickel complex were slightly modified by the extra anions, whereas the photophysical properties of the zinc complex appeared unchanged.
2H→1T Phase Engineering of Layered Tantalum Disulfides in Electrocatalysis: Oxygen Reduction Reaction
Authors: Luxa Jan , Mazánek Vlastimil , Pumera Martin , Lazar Petr , Sedmidubský David , Callisti Mauro , Polcar Tomáš , Sofer Zdeněk
Published: April 2017

Tremendous attention is currently being paid to renewable sources of energy. Transition‐metal dichalcogenides (TMDs) have been intensively studied for their promising catalytic activities in the hydrogen evolution reaction (HER) and the oxygen reduction reaction (ORR). In this fundamental work, we explored the catalytic properties of TMD family members 2H TaS2 and 1T TaS2. Our findings reveal that both polytypes exhibit poor HER performance, which is even more pronounced after electrochemical reduction/oxidation. Our experimental data show that 1T TaS2 has a lower overpotential at a current density of −10 mA cm−1, despite theoretical DFT calculations that indicated that the more favorable free energy of hydrogen adsorption should make “perfect” 2H TaS2 a better HER catalyst. Thorough characterization showed that the higher conductivity of 1T TaS2 and a slightly higher surface oxidation of 2H TaS2 explains this discrepancy. Moreover, changes in the catalytic activity after electrochemical treatment are addressed here. For the ORR in an alkaline environment, the electrochemical treatment led to an improvement in catalytic properties. With onset potentials similar to that of Pt/C catalysts, TaS2 was found to be an efficient catalyst for the ORR, rather than for proton reduction, in contrast to the behavior of Group 6 layered TMDs.
Nodular oncocytic hyperplasia: Can cytomorphology allow for the preoperative diagnosis of a nonneoplastic salivary disease?
Authors: Rooper Lisa M. , Onenerk Mine , Siddiqui Momin T. , Faquin William C. , Bishop Justin A. , Ali Syed Z.
Published: April 2017

BACKGROUND

Nodular oncocytic hyperplasia (oncocytosis) of the salivary glands is a benign process that does not inherently require surgical excision. However, cytologic findings in fine‐needle aspiration (FNA) of oncocytosis cases have not been well characterized previously, limiting preoperative identification.

METHODS

All available cases of oncocytosis with corresponding FNA specimens were identified from the pathology archives of 3 academic institutions. Clinical, cytologic, and histologic findings were tabulated for all cases.

RESULTS

Twelve cases of oncocytosis were identified from 11 patients, including 11 parotid FNA specimens and 1 submandibular FNA specimen. On the original diagnoses, 6 specimens were classified as benign, 4 as atypical, and 2 as nondiagnostic. Oncocytosis was listed in the differential diagnosis in only 1 case. Among diagnostic aspirates, 8 demonstrated low cellularity and 2 demonstrated moderate cellularity. All 10 cases demonstrated oncocytic cells in small to medium groups, with single cells in just 1 case. Spindled and squamous morphology were each noted in 3 cases. Four cases demonstrated cystic change and 1 showed background mucin without goblet cells. No necrosis or mitoses were observed.

CONCLUSIONS

Although oncocytosis demonstrates some overlap with Warthin tumor and oncocytoma, it lacks the diagnostic findings specific to oncocytic salivary gland malignancies such as salivary duct carcinoma, acinic cell carcinoma, mammary analog secretory carcinoma, and mucoepidermoid carcinoma. Despite current limitations in the understanding of oncocytic salivary gland lesions, the presence of a paucicellular specimen comprised of small groups of oncocytic cells should raise the possibility of oncocytosis in the differential diagnosis and can favor it in elderly patients with multiple salivary nodules. Cancer Cytopathol 2017;125:627‐34. © 2017 American Cancer Society.
CO2‐Assisted Solution‐Phase Selective Assembly of 2D WS2‐WO3⋅H2O and 1T‐2H MoS2 to Desirable Complex Heterostructures
Authors: Ren Yumei , Xu Qun , Wang Chongze , Zheng Xiaoli , Jia Yu , Qi Yuhang , Zhou Yunchun , Yang Xinan , Zhang Zhenyu
Published: April 2017

Precise control of the lateral and vertical integration of two‐dimensional (2D) heterostructures is exciting for novel electronic and photovoltaic applications. Fabricating assemblies of high‐quality heterostructures with desirable compositions and sequences is challenging. In this work, with the assistance of supercritical CO2 (SC CO2), we successfully prepared the complex heterostructures of WS2‐WO3⋅H2O/1T‐2H MoS2 with selective stacking assembly. Thanks to the unique properties of SC CO2, which can help to construct a unique solvent system where the hydrophilic or hydrophobic structure for the 2D layer heterostructure can be chosen, 2H‐WS2/2H‐MoS2 assemblies are formed efficiently as the preferred van der Waals heterojunctions. A superior photoelectrochemical activity toward hydrogen evolution based on such the quaternary heterostructures is achieved due to their strong interlayer electronic coupling as well as the increased conductivity and active sites in the heterostructures.
Magnetic Response of Aromatic Rings Under Rotation: Aromatic Shielding Cone of Benzene Upon Different Orientations of the Magnetic Field
Authors: Papadopoulos A. G. , Charistos N. D. , Muñoz‐Castro A.
Published: April 2017

The induced shielding cone is one of the most characteristic aspects of aromatic species. Herein, we explore its behavior under different orientations of the applied magnetic field by evaluating the overall and dissected π‐ and σ‐electron contributions. Our results shed light onto the orientation dependence behavior of the shielding cone, unraveling a characteristic pattern upon rotation of the aromatic ring. This pattern decreases the long range of the magnetic response, such that it resembles the behavior under constant molecular tumbling in solution.