bluuebunny/crossref_metadata_2025 huggingface dataset:
One‐Step Synthesis of 2,5‐Diaminoimidazoles and Total Synthesis of Methylglyoxal‐Derived Imidazolium Crosslink (MODIC)
Authors: Sabbasani Venkata R. , Wang Kung‐Pern , Streeter Matthew D. , Spiegel David A.
Published: November 2019

Here we describe a general method for the synthesis of 2,5‐diaminoimidazoles, which involves a thermal reaction between α‐aminoketones and substituted guanylhydrazines without the need for additives. As one of the few known ways to access the 2,5‐diaminoimidazole motif, our method greatly expands the number of reported diaminoimidazoles and further supports our previous observations that these compounds spontaneously adopt the non‐aromatic 4(H) tautomer. The reaction works successfully on both cyclic and acyclic amino ketone starting materials, as well as a range of substituted guanylhydrazines. Following optimization, the method was applied to the efficient synthesis of the advanced glycation end product (AGE) methylglyoxal‐derived imidazolium crosslink (MODIC). We expect that this method will enable rapid access to a variety of biologically important 2,5‐diaminoimidazole‐containing products.
Negative Charge as a Lens for Concentrating Antiaromaticity: Using a Pentagonal “Defect” and Helicene Strain for Cyclizations
Authors: Zhou Zheng , Kawade Rahul Kisan , Wei Zheng , Kuriakose Febin , Üngör Ökten , Jo Minyoung , Shatruk Michael , Gershoni‐Poranne Renana , Petrukhina Marina A. , Alabugin Igor V.
Published: November 2019

Incorporation of a five‐membered ring into a helicene framework disrupts aromatic conjugation and provides a site for selective deprotonation. The deprotonation creates an anionic cyclopentadienyl unit, switches on conjugation, leads to a >200 nm red‐shift in the absorbance spectrum and injects a charge into a helical conjugated π‐system without injecting a spin. Structural consequences of deprotonation were revealed via analysis of a monoanionic helicene co‐crystallized with {K+(18‐crown‐6)(THF)} and {Cs+2(18‐crown‐6)3}. UV/Vis‐monitoring of these systems shows a time‐dependent formation of mono‐ and dianionic species, and the latter was isolated and crystallographically characterized. The ability of the twisted helicene frame to delocalize the negative charge was probed as a perturbation of aromaticity using NICS scans. Relief of strain, avoidance of antiaromaticity, and increase in charge delocalization assist in the additional dehydrogenative ring closures that yield a new planarized decacyclic dianion.
Tandem Use of Optical Sensing and Machine Learning for the Determination of Absolute Configuration, Enantiomeric and Diastereomeric Ratios, and Concentration of Chiral Samples
Authors: De los Santos Zeus A. , MacAvaney Sean , Russell Katina , Wolf Christian
Published: November 2019

We have developed an optical method for accurate concentration, er, and dr analysis of amino alcohols based on a simple mix‐and‐measure workflow that is fully adaptable to multiwell plate technology and microscale analysis. The conversion of the four aminoindanol stereoisomers with salicylaldehyde to the corresponding Schiff base allows analysis of the dr based on a change in the UV maximum at 420 nm that is very different for the homo‐ and heterochiral diastereomers and of the concentration of the sample using a hypsochromic shift of another absorption band around 340 nm that is independent of the analyte stereochemistry. Subsequent in situ formation of CuII assemblies in the absence and presence of base enables quantification of the er values for each diastereomeric pair by CD analysis. Applying a linear programming method and a parameter sweep algorithm, we determined the concentration and relative amounts of each of the four stereoisomers in 20 samples of vastly different stereoisomeric compositions with an averaged absolute percent error of 1.7 %.
Comparison in composite performance after thermooxidative aging of injection molded polyamide 6 with glass fiber, talc, and a sustainable biocarbon filler
Authors: Jubinville Dylan , Abdelwahab Mohamed , Mohanty Amar K. , Misra Manjusri
Published: November 2019

Degradation is an unavoidable part of a material's life making it important to both monitor and control the aging behavior of plastics. This study compares thermooxidative degraded composites of a novel bio‐based and sustainable filler, Biocarbon (MBc), against that of traditional and commercially available fillers (glass fiber and talc) used in the automotive industry. The influence of thermooxidative degradation on the composites was studied under accelerated heat aging for 1000 h at 140°C. The mechanical properties of the composites were evaluated using notched Izod impact as well as both tensile and flexural tests. Morphological structure of the composites was investigated using a scanning electron microscopy. Dynamic mechanical analysis and differential scanning calorimetry were used to evaluate the physical transitions both before and after aging. The glass‐filled composites displayed the best performance; while, both the talc and biocarbon composites possessed similar strength and ductility performances. Advantageously, the biocarbon composites experienced an 11% reduction in density as compared to talc‐filled composites with similar weight content. After aging, all composites exhibited reduced tensile and flexural strengths ranging from 5 to 67% partly due to chain scission. Whereas, the modulus of all composites increased with a range of 1–24% due to an annealing effect. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci.2020,137, 48618.
Amphiphilic PLGA‐PEG‐PLGA triblock copolymer nanogels varying in gelation temperature and modulus for the extended and controlled release of hyaluronic acid
Authors: Osorno Laura L. , Maldonado Daniel E. , Whitener Ricky J. , Brandley Alyssa N. , Yiantsos Alex , Medina Jamie D. R. , Byrne Mark E.
Published: November 2019

Different compositional parameters of poly(D,L‐lactic‐co‐glycolic acid)‐b‐poly(ethylene glycol) triblock copolymers (PLGA‐PEG) were varied to analyze their effect on gel formation and mechanical properties. Parameters such as hydrophilic/hydrophobic ratio (PLGA/PEG ratio), lactic acid/glycolic acid ratio (LA/GA ratio), PEG molecular weight (PEG Mw), polymer solution concentration, copolymer molecular weight (Mw), and polydispersity index (PDI) were studied in this work. For copolymers with PEG Mw of 1500 Da, gelation temperature (34–37 °C) was affected by D,L‐LA/GA ratio and Mw; while modulus was affected by LA/GA ratio, Mw, and Mn. Based on the parametric study, an injectable, thermoresponsive hyaluronic acid (HA) delivery platform was designed for ocular applications. PLGA‐PEG copolymers with D,L‐LA/GA ratio of 15/1, PLGA/PEG ratio of 2/1, PEG Mw of 1500 Da, and Mw of about 6 KDa gelled at 35 °C, were optically transparent, had a modulus less than 350 Pa and were used for HA release studies. This work also demonstrates, for the first time, an extended and controlled release of HA, beyond 2 weeks, from injectable hydrogels modified with a noncovalent interacting agent, poly(L‐lysine). Smaller PLL chains slowed down the HA release kinetics, while larger PLL chains produced a release profile similar to the nonmodified hydrogels. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020, 137, 48678.
Aramid pulp reinforced hydrogenated nitrile butadiene rubber composites with ionic liquid compatibilizers
Authors: Demétrio da Silva Vinícius , Barros Ítalo Ribeiro de , Conceição Débora K. Silva da , Almeida Kauana Nunes de , Schrekker Henri Stephan , Amico Sandro C. , Jacobi Marly M.
Published: November 2019

Although carbon black is an effective reinforcement for most rubbers, its replacement by other fillers would be beneficial. Aramid fibers are used in a range of applications in the rubber industry, providing dimensional stability prior to vulcanization and improving the mechanical properties of the elastomeric product. Nevertheless, their relatively inert surface is an obstacle in the exploitation of their full potential. In this work, two ionic liquids were investigated as compatibilizers in the preparation of hydrogenated nitrile butadiene rubber composites with aramid pulp and carbon black fillers. The materials were characterized using swelling, hardness and tensile tests, differential scanning calorimetry, thermal gravimetric analysis, and infrared spectroscopy. The carbon black‐free composite prepared from aramid pulp treated with 1.0 wt% of 1‐carboxymethyl‐3‐methylimidazolium chloride outperformed all other studied materials, presenting a higher modulus at 100% strain (7.31 MPa), while maintaining high strain at break. Thus, ionic liquids were found to potentialize the aramid reinforcement effect in these rubber composites. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci.2019,137, 48702.
Ertüchtigung seismisch beschädigter Rahmenknoten aus Stahlbeton mittels FRP‐Filamentbündelverbindungen
Authors: Golias Emmanuil , Lindenthal Heiko , Schlüter Franz‐Hermann , Karabinis Athanasios I.
Published: November 2019

In Gebieten mittlerer und hoher seismischer Gefährdung werden in Stahlbetonskelettkonstruktionen bei Erdbebenereignissen häufig die Rahmenknoten (Anschluss Stütze/Riegel) beschädigt und müssen anschließend für eine weitere Nutzung der Konstruktion instand gesetzt werden.

Im Folgenden werden ein neues Sanierungsverfahren und experimentelle Untersuchungen hierzu vorgestellt. Prüfkörper mit zuvor erzeugter moderater Vorschädigung werden mit hochfestem Reparaturmörtel und Filamentbündelverbindungen (C‐FRP) im Knotenpunkt Stütze/Riegel verstärkt. Es werden die Versuchsergebnisse eines Prüfkörpers im Maßstab 1:1 im ungeschädigten Zustand (JA1V) sowie im nach Vorschädigung verstärkten Zustand (JA1FXb) ausgewertet und verglichen. Zur Simulation der Erdbebenwirkungen wird dabei zunächst der ungeschädigte Prüfkörper auf dem Prüfstand zyklisch belastet. Anschließend wird derselbe, durch den ersten Versuch vorgeschädigte Prüfkörper mit Filamentbündelverbindungen (C‐FRP) im Knoten und im Unterzugbereich verstärkt und auf dem Prüfstand erneut den identischen zyklischen Belastungen ausgesetzt. Die wesentlichen Messergebnisse beider Versuche werden aufgezeichnet und hinsichtlich Tragfähigkeit, Steifigkeiten und absorbierter Energie (Fähigkeit zur Energiedissipation) miteinander verglichen. Des Weiteren wird die angewendete Sanierungstechnik im Detail vorgestellt.
Novel and de novo mutation of PCDH19 in Girls Clustering Epilepsy
Authors: Yang Li , Liu Jing , Su Quanping , Li Yufen , Yang Xiaofan , Xu Liyun , Tong Lili , Li Baomin
Published: November 2019

Background

PCDH19 has become the second most relevant gene in epilepsy after SCN1A. Seizures often provoked by fever.

Methods

We screened 152 children with fever‐sensitive epilepsy for gene detection. Their clinical information was followed up.

Results

We found eight PCDH19 point mutations (four novel and four reported) and one whole gene deletion in 10 female probands (seven sporadic cases and three family cases) who also had cluster seizures. The common clinical features of 16 patients in 10 families included fever‐sensitive and cluster seizures, mainly focal or tonic‐clonic seizures, and absence of status epilepticus, normal intelligence, or mild‐to‐moderate cognitive impairment, the onset age ranges from 5 months to 20 years. Only four patients had multiple or focal transient discharges in interictal EEG. Focal seizures originating in the frontal region were recorded in four patients, two from the parietal region, and one from the occipital region.

Conclusion

PCDH19 mutation can be inherited or de novo. The clinical spectrum of PCDH19 mutation includes PCDH19 Girls Clustering Epilepsy with or without mental retardation, psychosis, and asymptomatic male. The onset age of PCDH19 Girls Clustering Epilepsy can range from infancy to adulthood. Sisters in the same family may be sensitive to the same antiepileptic drugs. And our report expands the mutation spectrum of PCDH19 Girls Clustering Epilepsy.
Development and pilot evaluation of a personalized decision support intervention for low risk prostate cancer patients
Authors: Belkora Jeffrey , Chan June M. , Cooperberg Matthew R. , Neuhaus John , Stupar Lauren , Weinberg Tia , Broering Jeanette M. , Tenggara Imelda , Cowan Janet E. , Rosenfeld Stan , Kenfield Stacey A. , Van Blarigan Erin L. , Simko Jeffry P. , Witte John , Carroll Peter R.
Published: November 2019

Objectives

Development and pilot evaluation of a personalized decision support intervention to help men with early‐stage prostate cancer choose among active surveillance, surgery, and radiation.

Methods

We developed a decision aid featuring long‐term survival and side effects data, based on focus group input and stakeholder endorsement. We trained premedical students to administer the intervention to newly diagnosed men with low‐risk prostate cancer seen at the University of California, San Francisco. Before the intervention, and after the consultation with a urologist, we administered the Decision Quality Instrument for Prostate Cancer (DQI‐PC). We hypothesized increases in two knowledge items from the DQI‐PC: How many men diagnosed with early‐stage prostate cancer will eventually die of prostate cancer? How much would waiting 3 months to make a treatment decision affect chances of survival? Correct answers were: “Most will die of something else” and “A little or not at all.”

Results

The development phase involved 6 patients, 1 family member, 2 physicians, and 5 other health care providers. In our pilot test, 57 men consented, and 44 received the decision support intervention and completed knowledge surveys at both timepoints. Regarding the two knowledge items of interest, before the intervention, 35/56 (63%) answered both correctly, compared to 36/44 (82%) after the medical consultation (P = .04 by chi‐square test).

Conclusions

The intervention was associated with increased patient knowledge. Data from this pilot have guided the development of a larger scale randomized clinical trial to improve decision quality in men with prostate cancer being treated in community settings.
Value‐based pricing: Toward achieving a balance between individual and population gains in health benefits
Authors: Parmar Ambica , Jiao Tina , Saluja Ronak , Chan Kelvin K. W.
Published: November 2019

Objectives

Value‐based pricing of oncology drugs provides a best estimate for the price of a drug, as it relates to the benefits it provides for individual patients. To date, the impact of value‐based pricing to reference cost‐effectiveness thresholds (λ) on individual and population‐level health benefits remains uncharacterized. The current study examined the potential benefits of value‐based pricing by quantifying the incremental net health benefit (INHB) of publicly funded oncology drugs, if funding occurred at manufacturer‐submitted price without value‐based pricing.

Methods

Pan‐Canadian Oncology Drug Review (pCODR) submissions were reviewed to identify eligible drug indications from which final economic guidance panel reports were reviewed for incremental costs (ΔC) and quality‐adjusted life‐years (ΔQALY) from manufacturer‐submitted, pCODR lower‐limit (pCODR‐LL) and upper‐limit (pCODR‐UL) re‐analyzed estimates. Annual number of cases in Ontario for each drug indication was obtained from population databases. Annual QALY gain per drug indication was determined by (ΔQALY × cases). Population QALY gain/loss in the absence of value‐based pricing to reference λ was estimated by the INHB: (INHB = [ΔQALY − (ΔC/λ)] × cases).

Results

In total, 34 drug indications (4629 cases) were identified. Annual gain in QALYs for the funded drug indications using manufacturer, pCODR‐LL, and pCODR‐UL estimates was 1851, 1617, and 1301, respectively. At a λ $100 000/QALY, funding in the absence of value‐based pricing resulted in loss of 2311, 2519, and 2604 QALYs. This would result in a provincial net annual loss of 460, 902, and 1303 QALYs.

Conclusions

Despite an annual gain in QALY per funded drug indication, a net loss in QALY for the province, in the absence of value‐based pricing, was demonstrated. Supportive evidence exists for value‐based pricing toward the promotion of health benefits for the greater population.
Potent anti‐myeloma activity of the TOPK inhibitor OTS514 in pre‐clinical models
Authors: Stefka Andrew T. , Johnson David , Rosebeck Shaun , Park Jae‐Hyun , Nakamura Yusuke , Jakubowiak Andrzej J.
Published: November 2019

Multiple myeloma (MM) continues to be considered incurable, necessitating new drug discovery. The mitotic kinase T‐LAK cell‐originated protein kinase/PDZ‐binding kinase (TOPK/PBK) is associated with proliferation of tumor cells, maintenance of cancer stem cells, and poor patient prognosis in many cancers. In this report, we demonstrate potent anti‐myeloma effects of the TOPK inhibitor OTS514 for the first time. OTS514 induces cell cycle arrest and apoptosis at nanomolar concentrations in a series of human myeloma cell lines (HMCL) and prevents outgrowth of a putative CD138+ stem cell population from MM patient‐derived peripheral blood mononuclear cells. In bone marrow cells from MM patients, OTS514 treatment exhibited preferential killing of the malignant CD138+ plasma cells compared with the CD138− compartment. In an aggressive mouse xenograft model, OTS964 given orally at 100 mg/kg 5 days per week was well tolerated and reduced tumor size by 48%‐81% compared to control depending on the initial graft size. FOXO3 and its transcriptional targets CDKN1A (p21) and CDKN1B (p27) were elevated and apoptosis was induced with OTS514 treatment of HMCLs. TOPK inhibition also induced loss of FOXM1 and disrupted AKT, p38 MAPK, and NF‐κB signaling. The effects of OTS514 were independent of p53 mutation or deletion status. Combination treatment of HMCLs with OTS514 and lenalidomide produced synergistic effects, providing a rationale for the evaluation of TOPK inhibition in existing myeloma treatment regimens.
Whole exome sequencing reveals a de novo missense variant in EEF1A2 in a Rett syndrome‐like patient
Authors: Kaur Simranpreet , Van Bergen Nicole J. , Gold Wendy Anne , Eggers Stefanie , Lunke Sebastian , White Susan M. , Ellaway Carolyn , Christodoulou John
Published: November 2019

Using whole exome sequencing, we found a pathogenic variant in the EEF1A2 gene in a patient with a Rett syndrome‐like (RTT‐like) phenotype, further confirming the association between EEF1A2 and Rett syndrome RTT and RTT‐like phenotypes.
Reductive Cycloisomerization of Diynes by Supported Palladium Catalysts and Subsequent [4+2] Cycloaddition for One‐Pot Synthesis of Cyclohexenes
Authors: Miura Hiroki , Tanaka Yumi , Nakahara Karin , Shishido Tetsuya
Published: November 2019

Abstract: Supported Pd nanoparticles catalyzed the reductive cycloisomerization of diynes to give 1,3‐dienes, and subsequent intermolecular [4+2] cycloaddition with dienophiles led to cyclohexene derivatives. Various diynes and dienophiles participated in the one‐pot reaction to give the corresponding products in good to high yields. Al2O3‐supported Pd catalysts were highly tolerant toward air and reusable.
Trifluoromethyl Derivatives of Elusive Fullerene C98
Authors: Tamm Nadezhda B. , Guan Runnan , Yang Shangfeng , Troyanov Sergey I.
Published: November 2019

Data concerning the isomeric composition of C98 and the chemistry of C98 derivatives are scarce due to very low abundance of C98 in the fullerene soot. Trifluoromethylation of C98‐containing mixtures followed by HPLC separation of CF3 derivatives and single crystal X‐ray diffraction study resulted in structural characterization of four compounds C98(248)(CF3)18/20, C98(116)(CF3)18, and C98(120)(CF3)20. To date, these compounds represent the largest fullerenes isolated as CF3 derivatives with experimentally determined molecular structures. The addition patterns of C98(CF3)18/20 are discussed in detail revealing the stabilizing factors, such as isolated double C=C bonds and benzenoid rings on C98 fullerene cages. A detailed comparison with the addition patterns of the known C98Cln allowed us to contribute to the better understanding the chemistry of elusive C98 fullerene.
Mobile Sensoren für die Biotechnologie – Ortsunabhängige, miniaturisierte Prozessmessung
Authors: Lauterbach Tim , Ziebart Nandor , Bley Thomas , Walther Thomas , Lenk Felix
Published: November 2019

Aufgrund verschiedenster Reaktorformen im Bereich der Biotechnologie liefern gewöhnliche Stabsonden unzureichend repräsentative Messergebnisse. In dieser Publikation werden neuartige mobile kugelförmige Sensoreinheiten mit einem Gesamtdurchmesser von 7,9 mm vorgestellt. Basierend auf Simulationen wurden diese in ihrer Dichte für die beste Verteilung im wässrigen Medium optimiert. Darüber hinaus wurde ermittelt, welche Auswirkungen unterschiedliche Rührgeschwindigkeiten in typischen Bioreaktoren auf die Verteilung der Sonden haben. Anhand dreier Bioreaktortypen wird die Anwendbarkeit der hier vorgestellten Messsonden gezeigt.
Predicting risk of cardiovascular events 1 to 3 years post‐myocardial infarction using a global registry
Authors: Pocock Stuart J. , Brieger David , Gregson John , Chen Ji Y. , Cohen Mauricio G. , Goodman Shaun G. , Granger Christopher B. , Grieve Richard , Nicolau Jose C. , Simon Tabassome , Westermann Dirk , Yasuda Satoshi , Hedman Katarina , Rennie Kirsten L. , Sundell Karolina Andersson ,   for the TIGRIS Study Investigators
Published: November 2019

Background

Risk prediction tools are lacking for patients with stable disease some years after myocardial infarction (MI).

Hypothesis

A practical long‐term cardiovascular risk index can be developed.

Methods

The long‐Term rIsk, Clinical manaGement and healthcare Resource utilization of stable coronary artery dISease in post‐myocardial infarction patients prospective global registry enrolled patients 1 to 3 years post‐MI (369 centers; 25 countries), all with ≥1 risk factor (age ≥65 years, diabetes mellitus requiring medication, second prior MI, multivessel coronary artery disease, or chronic non‐end‐stage kidney disease [CKD]). Self‐reported health was assessed with EuroQoL‐5 dimensions. Multivariable Poisson regression models were used to determine key predictors of the primary composite outcome (MI, unstable angina with urgent revascularization [UA], stroke, or all‐cause death) over 2 years.

Results

The primary outcome occurred in 621 (6.9%) of 9027 eligible patients: death 295 (3.3%), MI 195 (2.2%), UA 103 (1.1%), and stroke 58 (0.6%). All events accrued linearly. In a multivariable model, 11 significant predictors of primary outcome (age ≥65 years, diabetes, second prior MI, CKD, history of major bleed, peripheral arterial disease, heart failure, cardiovascular hospitalization (prior 6 months), medical management (index MI), on diuretic, and poor self‐reported health) were identified and combined into a user‐friendly risk index. Compared with lowest‐risk patients, those in the top 16% had a rate ratio of 6.9 for the primary composite, and 18.7 for all‐cause death (overall c‐statistic; 0.686, and 0.768, respectively). External validation was performed using the Australian Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events registry (c‐statistic; 0.748, and 0.849, respectively).

Conclusions

In patients >1‐year post‐MI, recurrent cardiovascular events and deaths accrue linearly. A simple risk index can stratify patients, potentially helping to guide management.
Association between facility volume and mortality of patients with classic Hodgkin lymphoma
Authors: Goyal Gaurav , Tella Sri Harsha , Funni Shealeigh , Kommalapati Anuhya , Inselman Jonathan W. , Shah Nilay D. , Go Ronald S. , Ansell Stephen M.
Published: November 2019

Background

Prior studies in oncology have shown that a higher annual facility patient volume is associated with reduced mortality. Because classic Hodgkin lymphoma is uncommon but highly curable, this study used the National Cancer Database (2003‐2014) to analyze whether such a relationship exists for this disease.

Methods

The facilities were classified by quartiles, and random intercepts were used to account for clustering of patients within facilities. A Cox regression model was used to determine the volume‐outcome relationship.

Results

There were 47,633 patients with classic Hodgkin lymphoma treated at 1310 facilities. The first quartile (Q1), which included 58.4% of the facilities, treated 3 or fewer patients per year, whereas the fourth quartile (Q4), which included 5.9% of the facilities, treated more than 9 patients per year. Compared with the patients treated at Q4 facilities, those treated at lower quartile facilities had a higher risk of death (hazard ratio for the third quartile [HR], 1.19; 95% confidence interval [CI], 1.1‐1.29; HR for the second quartile, 1.28; 95% CI, 1.19‐1.38; HR for Q1, 1.29; 95% CI, 1.2‐1.39) after adjustments for all other factors (P < .0001). Compared with facilities treating 10 patients per year, facilities treating 40 patients per year had approximately 27% lower overall mortality rates.

Conclusions

Patients with classic Hodgkin lymphoma treated at high‐volume centers had lower overall mortality than those treated at lower volume centers. Because this is a highly curable malignancy, such differences may suggest a benefit from referral to higher volume facilities or the emulation of their care models.
Quantitative associations between health insurance and stage of melanoma at diagnosis among nonelderly adults in the United States
Authors: Abudu Boya , Cook Kaitlyn A. , Gershenwald Jeffrey E. , Cohen Philip R. , Geller Alan C.
Published: November 2019

Background

Health insurance plays a critical role in the accessibility to and quality of health care for patients with melanoma in the United States. Current knowledge regarding the association between insurance status and stage of melanoma is limited because few studies to date have simultaneously controlled for factors known to influence the risk of diagnosis of late‐stage melanoma. The current study was conducted to examine the association between health insurance status and stage of melanoma at the time of diagnosis in nonelderly adults, accounting for known risk factors for late‐stage diagnosis.

Methods

In this cross‐sectional study, the authors analyzed the National Cancer Data Base for cases of invasive melanoma diagnosed between 2004 and 2015 among individuals aged 26 to 64 years. Using the American Joint Committee on Cancer melanoma staging system, early‐stage melanoma was defined as stage I or stage II whereas late‐stage melanoma was defined as stage III or stage IV. Late‐stage diagnosis was the primary outcome compared across 4 insurance types (private, Medicaid, none, and unknown). Adjusted covariates were age, sex, race/ethnicity, educational level, income, year of diagnosis, number of comorbidities, and facility location. Logistic regression was used for univariable and multivariable analyses.

Results

Among 177,247 cases, individuals with Medicaid or no health insurance were found to have 3.12 (95% CI, 2.97‐3.28) and 2.21 (95% CI, 2.10‐2.33) times greater odds, respectively, of being diagnosed with late‐stage melanoma compared with individuals with private insurance after adjusting for risk factors in late‐stage diagnosis.

Conclusions

Future investigation into insurance disparities in the diagnosis of late‐stage melanoma may help to prioritize melanoma screening in populations with nonprivate insurance.
Poly(adenosine diphosphate ribose) polymerase inhibitors induce autophagy‐mediated drug resistance in ovarian cancer cells, xenografts, and patient‐derived xenograft models
Authors: Santiago‐O’Farrill Janice M. , Weroha S. John , Hou Xiaonan , Oberg Ann L. , Heinzen Ethan P. , Maurer Matthew J. , Pang Lan , Rask Philip , Amaravadi Ravi K. , Becker Sarah E. , Romero Ignacio , Rubio Ma Jesús , Matias‐Guiu Xavier , Santacana Maria , Llombart‐Cussac Antonio , Poveda Andrés , Lu Zhen , Bast Robert C.
Published: November 2019

Background

Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors exhibit promising activity against ovarian cancers, but their efficacy can be limited by acquired drug resistance. This study explores the role of autophagy in regulating the sensitivity of ovarian cancer cells to PARP inhibitors.

Methods

Induction of autophagy was detected by punctate LC3 fluorescence staining, LC3I to LC3II conversion on Western blot analysis, and electron microscopy. Enhanced growth inhibition and apoptosis were observed when PARP inhibitors were used with hydroxychloroquine, chloroquine (CQ), or LYS05 to block the hydrolysis of proteins and lipids in autophagosomes or with small interfering RNA against ATG5 or ATG7 to prevent the formation of autophagosomes. The preclinical efficacy of the combination of CQ and olaparib was evaluated with a patient‐derived xenograft (PDX) and the OVCAR8 human ovarian cancer cell line.

Results

Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) induced autophagy in a panel of ovarian cancer cells. Inhibition of autophagy with CQ enhanced the sensitivity of ovarian cancer cells to PARP inhibitors. In vivo, olaparib and CQ produced additive growth inhibition in OVCAR8 xenografts and a PDX. Olaparib inhibited PARP activity, and this led to increased reactive oxygen species (ROS) and an accumulation of γ‐H2AX. Inhibition of autophagy also increased ROS and γ‐H2AX and enhanced the effect of olaparib on both entities. Treatment with olaparib increased phosphorylation of ATM and PTEN while decreasing the phosphorylation of AKT and mTOR and inducing autophagy.

Conclusions

PARP inhibitor–induced autophagy provides an adaptive mechanism of resistance to PARP inhibitors in cancer cells with wild‐type BRCA, and a combination of PARP inhibitors with CQ or other autophagy inhibitors could improve outcomes for patients with ovarian cancer.
Geographic and demographic features of neuroendocrine tumors in the United States of America: A population‐based study
Authors: Gosain Rohit , Ball Somedeb , Rana Navpreet , Groman Adrienne , Gage‐Bouchard Elizabeth , Dasari Arvind , Mukherjee Sarbajit
Published: November 2019

Background

The incidence of neuroendocrine tumors (NETs) is rapidly rising. There are very few studies investigating the role of sociodemographic factors in NETs. This study was aimed at examining how geographic and sociodemographic characteristics shape outcomes in the NET population.

Methods

A retrospective analysis using the Surveillance, Epidemiology, and End Results database was performed, and the NET patient population from 1973 to 2015 was studied. Univariate and multivariable analyses were performed to evaluate patients' disease‐specific survival (DSS) and overall survival (OS). Geographic and sociodemographic factors, including the location of residence (urban area [UA] vs rural area [RA]), sex, race, insurance status, and marital status, were included in the analysis.

Results

A total of 53,034 patients (5517 in RAs and 47,517 in UAs) were included in the analysis. The incidence of NETs was found to be rising in both RAs and UAs but more rapidly in RAs (with the highest incidence in 2006‐2015: 5.93 per 100,000 in RAs vs 4.10 per 100,000 in UAs). Patients from RAs presented at advanced stages in comparison with patients from UAs (regional, 18% vs 16%; distant, 15% vs 13%; P < .01). In the multivariable model, RA patients had a trend toward poorer OS (hazard ratio, 1.05; P = .053) in comparison with UA patients. The multivariable analysis showed significantly worse DSS and OS for uninsured, single, and male patients in comparison with insured, married, and female patients, respectively.

Conclusions

This study has identified sociodemographic disparities in NET outcomes. Access to health care could be a potential contributing factor, although differences in environmental exposure, health behavior, and tumor biology could also be responsible.
Phase 1 Dose‐Escalation Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Tofacitinib in Japanese Healthy Volunteers
Authors: Miyoshi So , Krishnaswami Sriram , Toyoizumi Shigeyuki , Nakamura Hiroyuki , Zwillich Samuel H.
Published: November 2019

The aim of the study was to characterize the pharmacokinetics, safety, and tolerability of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis in healthy Japanese volunteers, and to compare these outcomes with those of healthy Western volunteers. Twenty‐five volunteers (Japanese, n = 16; Western [white], n = 9) were randomized to receive either 3 escalating single doses of tofacitinib (1, 5, and 30 mg), single‐dose tofacitinib (15 mg) followed by multiple doses (15 mg twice daily for 5 days), or placebo. No significant differences in systemic exposure to tofacitinib were detected between the 2 ethnicities. Following single tofacitinib 1, 5, and 30 mg doses, mean area under the plasma concentration–time curve from time zero to infinity ratio (Japanese/Western) values were 96.6%, 93.5%, and 95.6%, respectively. Similarly, mean maximum observed plasma concentration ratio values were 99.5%, 118%, and 119%, respectively. Mean renal clearance was also similar, ranging across doses from 134 mL/min (5 mg) to 162 mL/min (1 mg) in Japanese volunteers, and 124 mL/min (30 mg) to 160 mL/min (1 mg) in Western volunteers. In both ethnicities, most adverse events were mild. No serious adverse events or deaths were reported. The pharmacokinetics of tofacitinib were well characterized in healthy Japanese volunteers and were similar to those in Western volunteers.
Development of the Counseling Center Assessment of Psychological Symptoms‐Japanese version: Pilot study
Authors: Horita Ryo , Kawamoto Aki , Nishio Akihiro , Sado Tadahiro , Locke Benjamin D. , Yamamoto Mayumi
Published: November 2019

There is currently no reliable and valid multidimensional instrument for measuring psychological symptoms among Japanese university students. The purpose of this pilot study was to translate the Counseling Center Assessment of Psychological Symptoms‐62 (CCAPS‐62) into Japanese and evaluate its validity and reliability. Following robust translation procedures, the CCAPS‐Japanese was created. In the validation study, 2,758 undergraduate students from 11 universities (mean age = 19.08 ± 1.85 years) completed the CCAPS‐Japanese. The results of confirmatory factor analysis supported the theoretical eight‐factor structure model of the CCAPS‐Japanese with the exclusion of seven items. The decision to retain/remove items was made by evaluating factor loadings and model fit indices while considering cultural equivalence and structural validity. Using the finalized 55‐item CCAPS‐Japanese, further analyses demonstrated that the eight subscales had acceptable to good internal consistencies (α = .61–.89). Thus, the tool's validity and reliability were established. The CCAPS‐Japanese may be appropriate for assessing the psychological concerns of Japanese university students.
Evaluation of Current Regulation and Guidelines of Pharmacogenomic Drug Labels: Opportunities for Improvements
Authors: Shekhani Rawan , Steinacher Linda , Swen Jesse J. , Ingelman‐Sundberg Magnus
Published: November 2019

Pharmacogenomic drug labels in the Summary of Product Characteristics (SmPC) provide an instrument for clinical implementation of pharmacogenomics. We compared pharmacogenomic guidance by Clinical Pharmacogenetics Implementation Consortium (CPIC), Dutch Pharmacogenetics Working Group (DPWG), the US Food and Drug Administration (FDA), and by the European agencies the European Medicines Agency (EMA), College ter Beoordeling van Geneesmiddelen Medicines Evaluation Board (CBG‐MEB), and Federal Institute for Drugs and Medical Devices (FIDMD), collectively assigned as EMA/FIDMD+MEB shortened as EMA/FM. Of 54 drugs with an actionable gene–drug interaction in the CPIC and DPWG guidelines, only 50% had actionable pharmacogenomic information in the SmPCs and the agencies were in agreement in only 18% of the cases. We further compared 450 additional drugs, lacking CPIC or DPWG guidance, and found 126 actionable gene–drug labels by the FDA and/or the EMA/FM. Based on these 126 drugs in addition to the 54 above, the consensus of actionable pharmacogenomic labeling between the FDA and the EMA/FM was only 54%. In conclusion, guidelines provided by CPIC/DPWG are only partly implemented into the SmPCs and the implementation of pharmacogenomic drug labels into the clinics would strongly gain from a higher extent of consensus between agencies.
Natural Kaolin: Sustainable Technology for the Instantaneous and Energy‐Neutral Recycling of Anthropogenic Mercury Emissions
Authors: Ganguly Mainak , Tao Yuanyuan , Lee Bryan , Ariya Parisa A.
Published: November 2019

Kaolin, a natural and inexpensive clay mineral, is ubiquitous in soil, dirt, and airborne particles. Amongst four commonly available clay minerals, kaolin, as a result of its layered structure, is the most efficient natural gaseous Hg adsorbent to date (Langmuir maximum adsorption capacity Qm=574.08 μg g−1 and Freundlich Qm=756.49 μg g−1). The Hg uptake proceeds by homogeneous monolayer and heterogeneous processes. Hg physisorption on kaolin occurs in the dark, yet the adsorption rate is enhanced upon irradiation. The effects of several metal complexes, salts, halides and solvents on the Hg uptake were examined. The addition of CuCl2 particles leads to a significant enhancement of the Hg uptake capacity (>30 times) within second timescales and without irradiation. The physisorption with kaolin is switched to chemisorption upon the addition of CuCl2 to kaolin. This process is entirely reversible upon the addition of Zn/Sn granules at room temperature without any added energy. However, the investment of a small amount of renewable energy can speed up the process. This technology demonstrates the facile and efficient capture and recycling of elemental Hg0 from air. A wide range of metal particles and diverse physicochemical processes, which include the microphysics of nucleation, are herein examined to explore the potential reaction mechanism by using a suite of complementary analytical techniques. These new mechanistic insights open a new era of energy‐neutral environmental remediation based on natural soil/airborne particles.
Application of GATA 3 and TTF‐1 in differentiating parathyroid and thyroid nodules on cytology specimens
Authors: Shi Yan , Brandler Tamar C. , Yee‐Chang Melissa , Cangiarella Joan , Wei Xiao‐Jun , Leung Allen , Szeto Oliver , Deng Fang‐Ming , Liu Cheng Z. , Simsir Aylin , Sun Wei
Published: November 2019

Background

Differentiating parathyroid from thyroid lesions can be difficult on fine‐needle aspiration (FNA) due to overlapping cytomorphologic features. While the traditional parathyroid hormone (PTH) assays can help in the distinction, these tests may be cumbersome, particularly when the lesion is unexpected clinically and a needle wash is not collected at the time of FNA. Therefore, we chose to investigate the application of immunohistochemical staining (IHC) with GATA 3 and thyroid transcription factor‐1 (TTF‐1) on air‐dried cytology smears to distinguish parathyroid and thyroid lesions.

Methods

Air‐dried touch preparation (TP) slides were prepared from consecutively selected parathyroid and thyroid specimens. Thirteen FNA cases with the clinical concern for parathyroid lesions were also included in the study. IHC was performed on unstained and ultrafast Papanicolaou (UFP) stained air‐dried slides.

Results

On TP slides, GATA 3 expression was observed in all cases of parathyroid origin but no immunoreactivity was present in thyroid lesions. TTF‐1 expression was observed in all cases of thyroid origin but not in parathyroid lesions. GATA 3 and TTF‐1 expression of 13 FNA cases were consistent with the clinical impression or concurrent PTH tests.

Conclusions

IHC with GATA 3 and TTF‐1 on air‐dried cytology smears is a simple and effective way to differentiate parathyroid vs thyroid lesions on FNA. Air‐dried unstained and UFP‐stained slides perform equally well with IHC, but UFP‐stained slides provide the added benefit of morphologic evaluation and assessment of smear cellularity prior to IHC.
Partners coordinate territorial defense against simulated intruders in a duetting ovenbird
Authors: Diniz Pedro , Rech Gianlucca S. , Ribeiro Pedro H. L. , Webster Michael S. , Macedo Regina H.
Published: November 2019

Duets in breeding pairs may reflect a situation of conflict, whereby an individual answers its partner's song as a form of unilateral acoustic mate guarding or, alternatively, it may reflect cooperation, when individuals share in territory defense or safeguard the partnership. The degree of coordination between the sexes when responding to solo versus paired intruders may elucidate the function of songs in duets. We examined this issue in a study with rufous horneros (Furnarius rufus), a duetting, socially monogamous Neotropical species with low levels of extrapair paternity. We exposed social pairs during the nonbreeding season to playbacks of duets, male solos, female solos, and control heterospecific songs. Partners approached all conspecific stimuli together and responded by singing quickly, at higher rates and by coordinating ~80% of their songs into duets. For both sexes, most response variables (seven of nine) did not vary across conspecific treatments. These results suggest that partners duet and coordinate behaviors to cooperatively defend common territories. However, females spent more time in territorial vigilance, and partners were highly coordinated (correlated responses) in response to duets and female solos in comparison with male solos. This indicates that female intrusions (paired or solo) might be more threatening than male intrusions in the nonbreeding season, especially for territorial females, and that females are less cooperative with their partners in territory defense against male intruders.
Removal of grazers alters the response of tundra soil carbon to warming and enhanced nitrogen availability
Authors: Ylänne Henni , Kaarlejärvi Elina , Väisänen Maria , Männistö Minna K. , Ahonen Saija H. K. , Olofsson Johan , Stark Sari
Published: November 2019

The circumpolar Arctic is currently facing multiple global changes that have the potential to alter the capacity of tundra soils to store carbon. Yet, predicting changes in soil carbon is hindered by the fact that multiple factors simultaneously control processes sustaining carbon storage and we do not understand how they act in concert. Here, we investigated the effects of warmer temperatures, enhanced soil nitrogen availability, and the combination of these on tundra carbon stocks at three different grazing regimes: on areas with over 50‐yr history of either light or heavy reindeer grazing and in 5‐yr‐old exlosures in the heavily grazed area. In line with earlier reports, warming generally decreased soil carbon stocks. However, our results suggest that the mechanisms by which warming decreases carbon storage depend on grazing intensity: under long‐term light grazing soil carbon losses were linked to higher shrub abundance and higher enzymatic activities, whereas under long‐term heavy grazing, carbon losses were linked to drier soils and higher enzymatic activities. Importantly, under enhanced soil nitrogen availability, warming did not induce soil carbon losses under either of the long‐term grazing regimes, whereas inside exclosures in the heavily grazed area, also the combination of warming and enhanced nutrient availability induced soil carbon loss. Grazing on its own did not influence the soil carbon stocks. These results reveal that accounting for the effect of warming or grazing alone is not sufficient to reliably predict future soil carbon storage in the tundra. Instead, the joint effects of multiple global changes need to be accounted for, with a special focus given to abrupt changes in grazing currently taking place in several parts of the Arctic.
Multiple metrics of latitudinal patterns in insect pollination and herbivory for a tropical‐temperate congener pair
Authors: Baskett Carina A. , Schroeder Lucy , Weber Marjorie G. , Schemske Douglas W.
Published: November 2019

The biotic interactions hypothesis posits that biotic interactions are more important drivers of adaptation closer to the equator, evidenced by “stronger” contemporary interactions (e.g., greater interaction rates) and/or patterns of trait evolution consistent with a history of stronger interactions. Support for the hypothesis is mixed, but few studies span tropical and temperate regions while experimentally controlling for evolutionary history. Here, we integrate field observations and common garden experiments to quantify the relative importance of pollination and herbivory in a pair of tropical‐temperate congeneric perennial herbs. Phytolacca rivinoides and P. americana are pioneer species native to the Neotropics and the eastern United States, respectively. We compared plant–pollinator and plant–herbivore interactions between three tropical populations of P. rivinoides from Costa Rica and three temperate populations of P. americana from its northern range edge in Michigan and Ohio. For some metrics of interaction importance, we also included three subtropical populations of P. americana from its southern range edge in Florida. This approach confounds species and region but allows us, uniquely, to measure complementary proxies of interaction importance across a tropical‐temperate range in one system. To test the prediction that lower‐latitude plants are more reliant on insect pollinators, we quantified floral display and reward, insect visitation rates, and self‐pollination ability (autogamy). To test the prediction that lower‐latitude plants experience more herbivore pressure, we quantified herbivory rates, herbivore abundance, and leaf palatability. We found evidence supporting the biotic interactions hypothesis for most comparisons between P. rivinoides and north‐temperate P. americana (floral display, insect visitation, autogamy, herbivory, herbivore abundance, and young‐leaf palatability). Results for subtropical P. americana populations, however, were typically not intermediate between P. rivinoides and north‐temperate P. americana, as would be predicted by a linear latitudinal gradient in interaction importance. Subtropical young‐leaf palatability was intermediate, but subtropical mature leaves were the least palatable, and pollination‐related traits did not differ between temperate and subtropical regions. These nonlinear patterns of interaction importance suggest future work to link interaction importance to climatic or biotic thresholds. In sum, we found that the biotic interactions hypothesis was more consistently supported at the larger spatial scale of our study.
Partitioning the impact of environmental drivers and species interactions in dynamic aquatic communities
Authors: Musters C. J. M. , Ieromina Oleksandra , Barmentlo S. Henrik , Hunting Ellard R. , Schrama Maarten , Cieraad Ellen , Vijver Martina G. , van Bodegom Peter M.
Published: November 2019

Temperate aquatic communities are highly diverse and seasonally variable, due to internal biotic processes and environmental drivers, including human‐induced stressors. The impact of drivers on species abundance is supposed to differ fundamentally depending on whether populations are experiencing limitations, which may shift over the season. However, an integrated understanding of how drivers structure communities seasonally is currently lacking. In order to partition the effect of drivers, we used random forests to quantify interactions between all taxa and environmental factors using macrofaunal data from 18 agricultural ditches sampled over two years. We found that, over the agricultural season, taxon abundance became increasingly better predicted by the abundances of co‐occurring taxa and nutrients compared to other abiotic factors, including pesticides. Our approach provides fundamental insights in community dynamics and highlights the need to consider changes in species interactions to understand the effects of anthropogenic stressors.