bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of 2 Bromodomain and Extraterminal Inhibitors With Distinct Pharmacokinetic and Pharmacodynamic Profiles for the Treatment of Advanced Malignancies
Authors: Falchook Gerald , Rosen Seth , LoRusso Patricia , Watts Justin , Gupta Shilpa , Coombs Catherine C. , Talpaz Moshe , Kurzrock Razelle , Mita Monica , Cassaday Ryan , Harb Wael , Peguero Julio , Smith David C. , Piha-Paul Sarina A. , Szmulewitz Russ , Noel Marcus S. , Yeleswaram Swamy , Liu Phillip , Switzky Julie , Zhou Gongfu , Zheng Fred , Mehta Amitkumar
Published: September 2019

Purpose:

Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose–escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137).

Patients and Methods:

Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability.

Results:

Sixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329-101 has been completed; INCB 57643-101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses.

Conclusions:

INCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.
Discovery, Validation, and Application of Novel Methylated DNA Markers for Detection of Esophageal Cancer in Plasma
Authors: Qin Yi , Wu Chung W. , Taylor William R. , Sawas Tarek , Burger Kelli N. , Mahoney Douglas W. , Sun Zhifu , Yab Tracy C. , Lidgard Graham P. , Allawi Hatim T. , Buttar Navtej S. , Smyrk Thomas C. , Iyer Prasad G. , Katzka David A. , Ahlquist David A. , Kisiel John B.
Published: September 2019

Purpose:

The burden of esophageal cancer continues to rise, and noninvasive screening tools are needed. Methylated DNA markers (MDM) assayed from plasma show promise in detection of other cancers. For esophageal cancer detection, we aimed to discover and validate MDMs in tissue, and determine their feasibility when assayed from plasma.

Experimental Design:

Whole-methylome sequencing was performed on DNA extracted from 37 tissues (28 EC; 9 normal esophagus) and 8 buffy coat samples. Top MDMs were validated by methylation specific PCR on tissue from 76 EC (41 adeno, 35 squamous cell) and 17 normal esophagus. Quantitative allele-specific real-time target and signal amplification was used to assay MDMs in plasma from 183 patients (85 EC, 98 controls). Recursive partitioning (rPART) identified MDM combinations predictive of esophageal cancer. Validation was performed in silico by bootstrapping.

Results:

From discovery, 23 candidate MDMs were selected for independent tissue validation; median area under the receiver operating curve (AUC) for individual MDMs was 0.93. Among 12 MDMs advanced to plasma testing, rPART modeling selected a 5 MDM panel (FER1L4, ZNF671, ST8SIA1, TBX15, ARHGEF4) which achieved an AUC of 0.93 (95% CI, 0.89–0.96) on best-fit and 0.81 (95% CI, 0.75–0.88) on cross-validation. At 91% specificity, the panel detected 74% of esophageal cancer overall, and 43%, 64%, 77%, and 92% of stages I, II, III, and IV, respectively. Discrimination was not affected by age, sex, smoking, or body mass index.

Conclusions:

Novel MDMs assayed from plasma detect esophageal cancer with moderate accuracy. Further optimization and clinical testing are warranted.
Biomarker Analyses of Response to Cyclin-Dependent Kinase 4/6 Inhibition and Endocrine Therapy in Women with Treatment-Naïve Metastatic Breast Cancer
Authors: Finn Richard S. , Liu Yuan , Zhu Zhou , Martin Miguel , Rugo Hope S. , Diéras Véronique , Im Seock-Ah , Gelmon Karen A. , Harbeck Nadia , Lu Dongrui R. , Gauthier Eric , Huang Bartlett Cynthia , Slamon Dennis J.
Published: September 2019

Purpose:

Preclinical data identified the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib as synergistic with antiestrogens in inhibiting growth of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) human breast cancer models. This observation was validated clinically in the randomized, placebo-controlled, phase III PALOMA-2 study.

Experimental Design:

To determine markers of sensitivity and resistance to palbociclib plus letrozole, we performed comprehensive biomarker analyses, investigating the correlation with progression-free survival (PFS), on baseline tumor tissues from PALOMA-2.

Results:

Despite a broad biomarker search, palbociclib plus letrozole demonstrated consistent PFS gains versus placebo plus letrozole, with no single biomarker or cassette of markers associated with lack of benefit from combination treatment. Palbociclib plus letrozole confers efficacy on both luminal A and B patients. Higher CDK4 levels were associated with endocrine resistance which was mitigated by the addition of palbociclib, whereas lower PD-1 levels were associated with greater palbociclib plus letrozole benefit. Tumors with more active growth factor signaling, as exemplified by increased expression of FGFR2 and ERBB3 mRNA, appeared to be associated with greater PFS gain from the addition of palbociclib.

Conclusions:

These data underscore the importance of CDK4/6 signaling in HR+/HER2− breast cancer and suggest that the interplay between steroid hormone and peptide growth factor signaling could drive dependence on CDK4/6 signaling.

See related commentary by Anurag et al., p. 3
Direct Detection and Quantification of Neoantigens
Authors: Wang Qing , Douglass Jacqueline , Hwang Michael S. , Hsiue Emily Han-Chung , Mog Brian J. , Zhang Ming , Papadopoulos Nickolas , Kinzler Kenneth W. , Zhou Shibin , Vogelstein Bert
Published: September 2019

Many immunotherapeutic approaches under development rely on T-cell recognition of cancer-derived peptides bound to human leukocyte antigen molecules on the cell surface. Direct experimental demonstration that such peptides are processed and bound is currently challenging. Here, we describe a method that meets this challenge. The method entailed an optimized immunoprecipitation protocol coupled with two-dimensional chromatography and mass spectrometry. The ability to detect and quantify minute amounts of predefined antigens should be useful both for basic research in tumor immunology and for the development of rationally designed cancer vaccines.
Cardiac Arrest and Cardiopulmonary Resuscitation Outcome Reports: Update of the Utstein Resuscitation Registry Template for In-Hospital Cardiac Arrest: A Consensus Report From a Task Force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian and New Zealand Council on Resuscitation, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Southern Africa, Resuscitation Council of Asia)
Authors: Nolan Jerry P. , Berg Robert A. , Andersen Lars W. , Bhanji Farhan , Chan Paul S. , Donnino Michael W. , Lim Swee Han , Ma Matthew Huei-Ming , Nadkarni Vinay M. , Starks Monique A. , Perkins Gavin D. , Morley Peter T. , Soar Jasmeet ,   On behalf of the Utstein Collaborators
Published: September 2019

Utstein-style reporting templates provide a structured framework with which to compare systems of care for cardiac arrest. The 2004 Utstein reporting template encompassed both out-of-hospital and in-hospital cardiac arrest. A 2015 update of the Utstein template focused on out-of-hospital cardiac arrest, which makes this update of the in-hospital template timely. Representatives of the International Liaison Committee on Resuscitation developed an updated in-hospital Utstein reporting template iteratively by meeting face-to-face, by teleconference, and by online surveys between 2013 and 2018. Data elements were grouped by hospital factors, patient variables, pre-event factors, cardiac arrest and postresuscitation processes, and outcomes. Elements were classified as core or supplemental by use of a modified Delphi process. Variables were described as core if they were considered essential. Core variables should enable reasonable comparisons between systems and are considered essential for quality improvement programs. Together with core variables, supplementary variables are considered useful for research.
Cardiologist Participation in Accountable Care Organizations and Changes in Spending and Quality for Medicare Patients With Cardiovascular Disease
Authors: Sukul Devraj , Ryan Andrew M. , Yan Phyllis , Markovitz Adam A. , Nallamothu Brahmajee K. , Lewis Valerie A. , Hollingsworth John M.
Published: September 2019

Background:

Despite widespread adoption of Medicare accountable care organizations (ACOs), healthcare spending reductions have been modest. This may relate to variable participation in ACOs by specialist physicians, who disproportionately drive spending. To examine whether specialist participation in Medicare ACOs was associated with changes in healthcare spending and clinical quality, we analyzed national Medicare data.

Methods and Results:

Working with a 20% random sample of Medicare beneficiaries (2008 to 2015), we identified those with cardiovascular disease. We estimated linear regression models at the beneficiary-quarter level to evaluate changes in healthcare spending and clinical quality after the start of the Shared Savings Program in 2012. We then examined whether changes in spending and quality across ACOs were conditional on cardiologist participation. Our study included ≈1.6 million beneficiaries per year. Although the number of ACOs increased over the study period (from 114 in 2012 to 392 in 2015), the proportion with any cardiologist participation remained stable (from 80% in 2012 to 83% in 2015). Compared with unaligned beneficiaries, those cared for by ACOs without cardiologist participation were associated with a spending reduction (per quarter) of −$75 (95% CI, −$105 to −$46;
P
<0.001). Care receipt in an ACO with cardiologist participation was associated with an additional difference in spending of −$56 (95% CI, −$87 to −$25;
P
<0.001), driven by lower spending for skilled nursing facilities, evaluation and management services, procedural care, and testing. While heart failure admission rates were similar among aligned and unaligned beneficiaries, ACO care was associated with fewer all-cause readmissions (
P
<0.001) and emergency department visits (
P
<0.001). Rates of these outcomes did not vary by cardiologist participation.

Conclusions:

Annual spending for beneficiaries with cardiovascular disease was ≈$200 lower when cared for by ACOs with cardiologist participation (compared with those without). These spending reductions did not come at the expense of clinical quality.
NaHCO
3
Dilates Mouse Afferent Arteriole Via Na
+
/HCO
3
−
Cotransporters NBCs
Authors: Jiang Shan , Wang Ximing , Wei Jin , Zhang Gensheng , Zhang Jie , Xie Peng , Xu Lan , Wang Lei , Zhao Liang , Li Lingli , Wilcox Christopher S. , Chen Jianghua , Lai En Yin , Liu Ruisheng
Published: September 2019

Sodium bicarbonate has long been used to treat chronic kidney disease. It has been demonstrated to slow the decline in glomerular filtration rate in chronic kidney disease patient; however, the mechanisms are not completely understood. We hypothesized that NaHCO
3
dilates afferent arterioles (Af-Art) by stimulating nitric oxide (NO) release mediated by the Na
+
/HCO
3
−
cotransporter (NBC) contributing to the elevation in glomerular filtration rate. Isolated microperfused mouse renal Af-Art, preconstricted with norepinephrine (1 µmol/L), dilated 45±2% (n=6,
P
<0.05) in response to NaHCO
3
(44 mmol/L). Whereas, NaCl solution containing the same Na
+
concentration was not effective. The mRNA for NBCn1 and NBCe1 were detected in microdissected Af-Art using reverse transcription–polymerase chain reaction and quantitative polymerase chain reaction. The Af-Art intracellular pH measured with 2′,7′-bis-(2-carboxyethyl)-5-(and-6) carboxyfluorescein, acetoxymethyl ester increased significantly by 0.29±0.02 (n=6;
P
<0.05) in the presence of NaHCO
3
, which was blunted by N-cyanosulphonamide compound (S0859) that is an inhibitor of the NBC family. After clamping the intracellular pH with 10 μM nigericin, changing the bath solution pH from 7.4 to 7.8 still dilates the Af-Art by 53±4% (n=7;
P
<0.005) and increases NO generation by 22±3% (n=7;
P
<0.005). Both pH-induced NO generation and vasodilation were blocked by L-NG-Nitroarginine Methyl Ester. NaHCO
3
increased NO generation in Af-Art by 19±4% (n=5;
P
<0.005) and elevated glomerular filtration rate in conscious mice by 36% (233 versus 318 ul/min; n=9–10;
P
<0.0001). S0859 and L-NG-nitroarginine methyl ester blocked NaHCO
3
-induced increases in NO generation and vasodilation. We conclude that NBCn1 and NBCe1 are expressed in Af-Art and that NaHCO
3
dilates Af-Art via NBCs mediated by NO that increases the glomerular filtration rate.
On Functions Computed on Trees
Authors: Farhoodi Roozbeh , Filom Khashayar , Jones Ilenna Simone , Kording Konrad Paul
Published: September 2019

Any function can be constructed using a hierarchy of simpler functions through compositions. Such a hierarchy can be characterized by a binary rooted tree. Each node of this tree is associated with a function that takes as inputs two numbers from its children and produces one output. Since thinking about functions in terms of computation graphs is becoming popular, we may want to know which functions can be implemented on a given tree. Here, we describe a set of necessary constraints in the form of a system of nonlinear partial differential equations that must be satisfied. Moreover, we prove that these conditions are sufficient in contexts of analytic and bit-valued functions. In the latter case, we explicitly enumerate discrete functions and observe that there are relatively few. Our point of view allows us to compare different neural network architectures in regard to their function spaces. Our work connects the structure of computation graphs with the functions they can implement and has potential applications to neuroscience and computer science.
Thumos in Aristotle’s Politics VII.7
Authors: Deslauriers Marguerite
Published: September 2019

Aristotle claims that the citizens of the best city should be both intelligent and spirited at Politics VII.7 1327b19-38. While he treats intelligence as an unqualified good, thumos (‘spirit’) is valuable but problematic. This paper has two aims: (i) to consider the political value of spirit in Aristotle’s Politics and in particular to identify the ways in which it is both essential to political excellence and yet insufficient for securing it, and (ii) to use this analysis of the role of spirit in the political realm to explain Aristotle’s exclusion of women from political authority, even in the context of the household. I analyze spirit as a physical phenomenon and as a type of desire, before considering its moral and affective aspects. I then return to the role of spirit in political life and examine its importance for the activity of ruling. In the last section I consider the implications of this analysis of spirit for the social and political roles Aristotle assigns to men and women.
Aristotle’s Best City in the Context of His Concept of Aretē
Authors: Samaras Athanasios
Published: September 2019

The text of the Politics itself establishes beyond reasonable doubt that Aristotle’s best city is, in the philosopher’s own terms, an aristocracy: in Books III and IV Aristotle defines aristocracy as the regime that aims at the best, has virtue as its mark, does not allow citizenship to artisans and wage-earners, and distributes offices by merit. Books VII and VIII unequivocally attribute all these essential characteristics of aristocracy to Aristotle’s best city. In addition, his conception of the virtue of the citizens of this polis conforms to the traditional aristocratic interpretation of the term.

Aristotle – citizenship – kaloskagathos – aristocratic virtue
Politiques VII : un livre anti-platonicien
Authors: Pellegrin Pierre
Published: September 2019

The (quasi)-consensus of interpreters that gives books VII and VIII of the Politics a logical and chronological priority to books IV-VI and that claims that book VII advocates for an aristocratic regime must be abandoned. In fact, these last two books deal with questions which the legislator must know, but which fall short of any constitutional consideration. An image found in Book VII is illuminating: this book deals with the best conditions for life in the city and Aristotle compares it to the material that the craftsman best arranges before giving his product its form. Prior for us, these considerations are therefore posterior by nature to the constitutional analyzes of books IV-VI. In light of the Aristotelian doctrine of two different kinds of priority, we can say that the manuscripts, which place books VII and VIII at the end of the Politics, adopt an Aristotelian order.
Equality for Equals
Authors: Edge Matt
Published: September 2019

Discussions of the liberty of the ancients, in contemporary political theory, treat democratic freedom, and the political equality on which democracy was premised, as anathema to the liberty of the moderns. This article discusses ancient democratic liberty by referencing the theory of arithmetic equality preserved by Aristotle and Plato and suggests that we need to re-investigate this relationship in the interests of modern freedom. The article argues that, in fact, Greek, particularly Athenian, democratic ideas, construe freedom in a negative way and that democratic, arithmetic, accounts of equality are, at root, anti-oppressive and require further investigation in the name of justice for the moderns.
Searching for Statesmanship: a Corpus-Based Analysis of a Translated Political Discourse
Authors: Jones Henry
Published: September 2019

With its connotations of superior moral integrity, exceptional leadership qualities and expertise in the science of government, the modern ideal of statesmanship is most commonly traced back to the ancient Greek concept of πολιτικός (politikos) and the work of Plato and Aristotle in particular. Through an analysis of a large corpus of modern English translations of political works, built as part of the AHRC Genealogies of Knowledge project (http://genealogiesofknowledge.net/), this case-study aims to explore patterns that are specific to this translated discourse, with a view to understanding the crucial role played by translators in shaping its development and reception in society. It ultimately seeks to argue that the model of statesmanship presented in translations from ancient Greek is just as much a product of the receiving culture (and the social anxieties of Victorian Britain especially) as it is inherited from the classical world.
Just Silence in Plato’s Clitophon
Authors: Gassaway Shane
Published: September 2019

Plato’s Clitophon presents a confrontation between two alternative views of justice, one conventional and the other philosophical – and of Clitophon’s inability to move from the one to the other due to his confusion over the relationship between knowledge and virtue and his misconception of the path from ignorance to knowledge, which probably results from his ambition. The nature of this confusion is such that Clitophon can only overcome it by abandoning his submissive stance toward the authority of Socrates (or any other teacher), which fact, combined with the character of his appeal to Socrates for an answer to his difficulties makes any authentic verbal response from Socrates unlikely to help and to risk harm. Silence from Socrates at the conclusion of the dialogue would therefore exemplify the principle that it is not for the just to harm anyone.
Floral ontogeny of Illicium Lanceolatum (Schisandraceae) and its implications on carpel homology

Authors: ZHANG XIN , ZHANG ZHIXIANG , ZHAO ZHONG
Published: September 2019

There are two competing hypotheses for the origin of carpels. The traditional hypothesis favors a phyllosporous origin and regards a conduplicate carpel as an ancestral form that is the result of longitudinal folding of a leaf bearing ovules along its margins. Alternatively, the carpel formation is interpreted as the result of a fusion between an ovule-bearing branch and its subtending leaf-like structure. Illicium is a member of the Austrobaileyales, which are one of the three ANA lines that diverged before all other extant angiosperms. This genus with apocarpous gynoecium has various ancestral morphological characteristics in terms of carpel, ovule, and floral apex. Although various aspects of Illicium morphology have been previously investigated, many evolutionary characteristics remain poorly understood. In this study, the development of carpel, ovule, and floral apex of I. lanceolatum was studied using LM and SEM. The results showed that the ovule primordium originates in the axillary position between the flower axis and carpel wall. So the carpel of Illicium is a leaf-like structure that encircles the ovule. This kind of carpel favors the carpel as a result of fusion between two parts, ovule-bearing branch and its subtending leaf-like structure.
Neopestalotiopsis hadrolaeliae sp. nov., a new endophytic species from the roots of the endangered orchid Hadrolaelia jongheana in Brazil

Authors: FREITAS EMILIANE F. S. , DA SILVA MEIRIELE , BARROS MARCOS V. P. , KASUYA MARIA C. M.
Published: September 2019

A new endophytic fungal species, Neopestalotiopsis hadrolaeliae, is described from roots of Hadrolaelia jongheana, an endangered orchid species growing in Brazil. Multigene phylogenetic analyses coupled with morphological observations facilitated the identification of new species isolated from the roots of Hadrolaelia jongheana. Phylogenetic analyses based on ITS, TUB and TEF DNA sequences showed that the new taxon is different from reported Neopestalotiopsis species. Descriptions and illustrations and notes are provided for the new species, which we name herein as Neopestalotiopsis hadrolaeliae.
A review of the pleasing lacewing genus Dilar Rambur (Neuroptera, Dilaridae) from Central Asia
Authors: LI DI , ASPöCK HORST , ASPÖCK ULRIKE , LIU XINGYUE
Published: September 2019

The pleasing lacewing genus Dilar Rambur, 1838, is the only known representative of the family Dilaridae from Central Asia. Here we present a review of the five species of Dilar from Central Asia, Dilar hornei McLachlan, 1869, Dilar caesarulus H. Aspöck & U. Aspöck, 1967, Dilar kirgisus H. Aspöck & U. Aspöck, 1967, Dilar vartianorum H. Aspöck & U. Aspöck, 1967, and Dilar dochaner H. Aspöck & U. Aspöck, 1968. Remarkable intraspecific variations in male gonocoxite 10 are found in D. kirgisus and D. vartianorum. Re-descriptions of all the species are provided. Dilar indicus Monserrat, 1989, and Dilar similis Monserrat, 1989, are synonymized with D. vartianorum. A key to the species of Dilar from Central Asia is provided.
Synthesis of Mexican Symphypleona (Hexapoda: Collembola): updated checklist with ecological and geographical distribution
Authors: MAGAÑA-MARTÍNEZ CÉSAR S. , PALACIOS-VARGAS JOSÉ G. , NAVARRETE-HEREDIA JOSÉ L.
Published: September 2019

A taxonomic list of recorded Symphypleona from Mexico is presented. Data also includes a nomenclatorial update, distribution per political entity and habitat preferences. It is indicated that 28 genera and 73 species are currently distributed in 23 of the 32 states of Mexico. Quintana Roo represents the most diverse state (27 species) followed by Jalisco and Hidalgo (20 spp.). Reviews consulted indicate that eleven endemic species have been recorded so far from Mexico. According to the literature, one-third of the collected specimens across Mexico from leaf litter have yielded Symphypleona. The three most diverse genera recorded are, Sminthurides with 9 species, Sminthurinus and Sminthurus with 7 species each.
A new species of snook, Centropomus (Teleostei: Centropomidae), from northern South America, with notes on the geographic distribution of other species of the genus
Authors: CARVALHO-FILHO ALFREDO , DE OLIVEIRA JOICIANE , SOARES CAMILA , ARARIPE JULIANA
Published: September 2019

Centropomus irae sp. nov. (Centropomidae) is described from two localities in the state of Amapá, northern Brazil. The new species differs from all its congeners by the typically brown-colored lateral line, the relatively smaller mean interorbital width (4.1% of SL vs. 5.2–6.9%), mean snout length (8.9% of SL vs. 9.8–11.1%), mean diameter of the orbit (4.5% of SL vs. 5.4–7.3%), and mean mandible length (15.7% of SL vs.19.9–21.6%). The new species can also be distinguished from the similar Centropomus undecimalis by the number of scales around the caudal peduncle (18–23, usually 19–21, vs. 22–28, usually 24–27). With Centropomus irae sp. nov., seven species of the genus are now known to occur in the western Atlantic. The distribution of Centropomus in Brazilian waters is updated and a key to the species of this genus is presented. [Zoobank URL: urn:lsid:zoobank.org:act:3D497B38-48A5-4A6E-B377-6D57E82D4DE4[
A new species of king cricket Glaphyrosoma Brunner von Wattenwyl, 1888 (Orthoptera: Anostostomatidae: Glaphyrosomatini) from Costa Rica with behavioral observations
Authors: RICHARDSON STEVEN , TRIMM TRAVIS , PAREDES RANDELL , KOEHL JONATHAN , SONG HOJUN
Published: September 2019

A new king cricket species Glaphyrosoma stephanosoltis sp. nov. (Orthoptera: Anostostomatidae: Glaphyrosomatini) from mid-elevation tropical rainforests of Costa Rica is described. This new species represents the southernmost distribution of the genus Glaphyrosoma Brunner von Wattenwyl, 1888, which is widely distributed throughout Mexico, Guatemala, and Honduras. Biology of the new species is briefly described.
La terapia immunosoppressiva nel trapianto di rene
Authors: Tsalouchos Aris , Salvadori Maurizio
Published: September 2019

Immunosuppressive therapy in renal transplantation

Immunosuppressive therapy in renal transplantation can be distinguished in induction therapy and maintenance therapy.

Induction therapy is an intense immunosuppressive therapy administered at the time of kidney transplantation to reduce the risk of acute allograft rejection. In general, the induction immunosuppressive strategies used at kidney transplant centers fall into one of these two categories. One strategy relies upon high doses of conventional immunosuppressive agents, while the other utilizes antibodies directed against T-cell antigens in combination with lower doses of conventional agents.

Maintenance immunosuppressive therapy is administered to almost all kidney transplant recipients to help prevent acute rejection and loss of the renal allograft. Although an adequate level of immunosuppression is required to dampen the immune response to the allograft, the level of chronic immunosuppression is decreased over time (as the risk of acute rejection decreases) to help lower the overall risk of infection and malignancy; these risks directly correlate with the degree of overall immunosuppression.

The optimal maintenance immunosuppressive therapy in kidney transplantation is not established. The major immunosuppressive agents that are available in various combination regimens are glucocorticoids (primarily oral prednisone), azathioprine, mycophenolate mofetil (MMF), enteric-coated mycophenolate sodium (EC-MPS), cyclosporine (in non-modified or modified [microemulsion] form), Tacrolimus, everolimus, rapamycin (sirolimus), and Belatacept.
Computational method for importance measure of the k-out-of-n system based on stress–strength interference
Authors: Lyu Dong , Si Shubin , Cai Zhiqiang , Xie Liyang
Published: September 2019

Importance measures, which are used to evaluate the relative significance of various components to system reliability, have been widely applied in system reliability designs and risk assessments. This article deals with the importance measure for the k-out-of- n system of which components are loaded by common stress. Based on system-level stress–strength interference model, a new computational method for the Birnbaum importance measure is proposed for the k-out-of- n system. Then, two numerical examples are presented to further illustrate the proposed method and some key contents are discussed particularly as follows: (1) the importance measures for the system with s-identical components and nonidentical components are developed, (2) component importance changes as its own strength distribution parameters change and (3) the new method corrects the errors caused by ignoring the failure dependency.
Medication adherence, hospitalization, and healthcare resource utilization and costs in patients with pulmonary arterial hypertension treated with endothelin receptor antagonists or phosphodiesterase type‐5 inhibitors
Authors: Frantz Robert P. , Hill Jerrold W. , Lickert Cassandra A. , Wade Rolin L. , Cole Michele R. , Tsang Yuen , Drake William
Published: September 2019

Adherence to therapy for pulmonary arterial hypertension is essential to optimize patient outcomes, but data on real‐world adherence to different pulmonary arterial hypertension drug classes are limited. This retrospective database analysis evaluated relationships between adherence, hospitalization, and healthcare costs in pulmonary arterial hypertension patients treated with endothelin receptor antagonists or phosphodiesterase type‐5 inhibitors. From the IQVIA Adjudicated Health Plan Database, patients with pulmonary arterial hypertension were identified based on diagnostic codes and prescriptions for endothelin receptor antagonists (ambrisentan, bosentan, macitentan) or phosphodiesterase type‐5 inhibitors (sildenafil, tadalafil) approved for pulmonary arterial hypertension. Patients were assigned to the class of their most recently initiated (index) pulmonary arterial hypertension therapy between 1 January 2009 and 30 June 2015. Medication adherence was measured by proportion of days covered; patients with proportion of days covered ≥80% were considered adherent. The proportion of adherent patients was higher for endothelin receptor antagonists (571/755; 75.6%) than for phosphodiesterase type‐5 inhibitors (970/1578; 61.5%; P < 0.0001). In both groups, hospitalizations declined as proportion of days covered increased. Among adherent patients, those on endothelin receptor antagonists had a significantly lower hospitalization rate than those on phosphodiesterase type‐5 inhibitors (23.1% versus 28.5%, P = 0. 0218), fewer hospitalizations (mean (standard deviation) 0.4 (0.8) versus 0.5 (0.9); P = 0.02), and mean hospitalization costs during the six‐month post‐index ($9510 versus $15,726, P = 0.0318). Increasing adherence reduced hospitalization risk more for endothelin receptor antagonists than for phosphodiesterase type‐5 inhibitors (hazard ratio 0.176 versus 0.549, P = 0.001). Rates and numbers of rehospitalizations within 30 days post‐discharge were similar between groups. Mean total costs were higher with endothelin receptor antagonists than phosphodiesterase type‐5 inhibitors in all patients ($91,328 versus $72,401, P = 0.0003) and in adherent patients ($88,867 versus $56,300, P < 0.0001), driven by higher drug costs.
The double-hit signature identifies double-hit diffuse large B-cell lymphoma with genetic events cryptic to FISH
Authors: Hilton Laura K. , Tang Jeffrey , Ben-Neriah Susana , Alcaide Miguel , Jiang Aixiang , Grande Bruno M. , Rushton Christopher K. , Boyle Merrill , Meissner Barbara , Scott David W. , Morin Ryan D.
Published: September 2019

High-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/THs) include a group of diffuse large B-cell lymphomas (DLBCLs) with inferior outcomes after standard chemoimmunotherapy. We recently described a gene expression signature that identifies 27% of germinal center B-cell DLBCLs (GCB-DLBCLs) as having a double-hit–like expression pattern (DHITsig) and inferior outcomes; however, only half of these cases have both MYC and BCL2 translocations identifiable using standard breakapart fluorescence in situ hybridization (FISH). Here, 20 DHITsig+ GCB-DLBCLs apparently lacking MYC and/or BCL2 rearrangements underwent whole-genome sequencing. This revealed 6 tumors with MYC or BCL2 rearrangements that were cryptic to breakapart FISH. Copy-number analysis identified 3 tumors with MYC and 6 tumors with MIR17HG gains or amplifications, both of which may contribute to dysregulation of MYC and its downstream pathways. Focal deletions of the PVT1 promoter were observed exclusively among DHITsig+ tumors lacking MYC translocations; this may also contribute to MYC overexpression. These results highlight that FISH fails to identify all HGBL-DH/THs, while revealing a range of other genetic mechanisms potentially underlying MYC dysregulation in DHITsig+ DLBCL, suggesting that gene expression profiling is more sensitive for identifying the biology underlying poor outcomes in GCB-DLBCL.
National surveillance using mobile systems for health monitoring: complexity, functionality and feasibility
Authors: Singh Yages , Jackson Debra , Bhardwaj Sanjana , Titus Natasha , Goga Ameena
Published: September 2019

Background

Although the use of technology viz. mobile phones, personalised digital assistants, smartphones, notebook and tablets to monitor health and health care (mHealth) is mushrooming, only small, localised studies have described their use as a data collection tool. This paper describes the complexity, functionality and feasibility of mHealth for large scale surveillance at national and sub-national levels in South Africa, a high HIV-prevalence setting.

Methods

In 2010, 2011–12 and 2012–13 three nationally representative surveys were conducted amongst infants attending 580 facilities across all 51 districts, within all nine provinces of South Africa, to monitor the effectiveness of the programme to prevent mother-to-child transmission of HIV (PMTCT). In all three surveys a technical protocol and iterative system for mobile data collection was developed. In 2012–13 the system included automated folders to store information about upcoming interviews. Paper questionnaires were used as a back-up, in case of mHealth failure. These included written instructions per question on limits, skips and compulsory questions. Data collectors were trained on both systems.

Results

In the 2010, 2011–12 and 2012–2013 surveys respectively, data from 10,554, 10,071, and 10,536 interviews, and approximately 186 variables per survey were successfully uploaded to 151 mobile phones collecting data from 580 health facilities in 51 districts, across all nine provinces of South Africa. A technician, costing approximately U$D20 000 p.a. was appointed to support field-based staff. Two percent of data were gathered using paper- questionnaires. The time needed for mHealth interviews was approximately 1,5 times less than the time needed for paper questionnaires 30–45 min versus approximately 120 min (including 60–70 min for the interview with an additional 45 min for data capture). In 2012–13, 1172 data errors were identified via the web-based console. There was a four-week delay in resolving data errors from paper-based surveys compared with a 3-day turnaround time following direct capture on mobile phones.

Conclusion

Our experiences demonstrate the feasibility of using mHealth during large-scale national surveys, in the presence of a supportive data management team. mHealth systems reduced data collection time by almost 1.5 times, thus reduced data collector costs and time needed for data management.
Longitudinal adherence to maternal antiretroviral therapy and infant Nevirapine prophylaxis from 6 weeks to 18 months postpartum amongst a cohort of mothers and infants in South Africa
Authors: Larsen Anna , Magasana Vuyolwethu , Dinh Thu-Ha , Ngandu Nobubelo , Lombard Carl , Cheyip Mireille , Ayalew Kassahun , Chirinda Witness , Kindra Gurpreet , Jackson Debra , Goga Ameena
Published: September 2019

Background

Despite improved policies to prevent mother-to-child HIV transmission (MTCT), adherence to maternal antiretroviral therapy (ART) and infant Nevirapine prophylaxis (NVP) is low in South Africa. We describe ART adherence amongst a cohort of HIV-positive mothers and HIV-exposed but uninfected infants from 6 weeks until 18 months post-delivery and identify risk factors for nonadherence.

Methods

Data were collected in 2012–2014 through a nationally representative survey of PMTCT effectiveness. Mother-infant pairs were enrolled during the infant’s first immunization visit at 6 weeks. Mothers and HIV-exposed infants (2811 pairs) were followed to 18 months at 3-month intervals. Mothers who self-reported being on ART at 6 weeks postpartum (N = 1572 (55.9%)) and infants on NVP at 6 weeks (N = 2370 (84.3%)) were eligible for this analysis and information about their adherence was captured at each interview they attended thereafter. We defined nonadherence within each 3-month interval as self-report of missing > 5% of daily ART/NVP doses, estimated adherence using a Cox survival curve with Andersen & Gill setup for recurring events, and identified risk factors for nonadherence with an extended Cox regression model (separately for mothers and infants) in Stata 13. Results are not nationally representative as this is a subgroup analysis of the follow-up cohort.

Results

Amongst mothers on ART at 6 weeks postpartum, cumulative adherence to maternal ART until 18 months was 63.4%. Among infants on NPV at 6 weeks postpartum, adherence to NVP was 74.5%.. Risk factors for nonadherence to maternal ART, controlling for other factors, included mother’s age (16–24 years vs. ≥34 years, adjusted Hazard Ratio (aHR): 1.9, 95% CI: 1.4–2.5), nondisclosure of HIV status to anyone (nondisclosure vs. disclosure: aHR: 1.7, 95% CI: 1.3–2.1), and timing of ART initiation (initiated ART after delivery vs. initiated ART before delivery: aHR: 1.6, 95% CI: 1.3–2.0). Provincial variation was seen in nonadherence to infant NVP, controlling for other factors.

Conclusion

Maintaining ART adherence until 18 months postpartum remains a crucial challenge, with maternal ART adherence among the six week maternal ART cohort below 65% and infant NVP adherence among breastfeeding infants in this cohort below 75%.This is gravely concerning, given the global policy shift to lifelong ART amongst pregnant and lactating women, and the need for extended infant prophylaxis amongst mothers who are not virally suppressed. Our findings suggest that young mothers and mothers who do not disclose their status should be targeted with messages to improve adherence, and that late maternal ART initiation (after delivery) increases the risk of maternal nonadherence.
Correction to: Validity and reliability of serratus anterior hand held dynamometry
Authors: IJspeert Jos , Kerstens Hans C. J. W. , Janssen Renske M. J. , Geurts Alexander C. H. , van Alfen Nens , Groothuis Jan T.
Published: September 2019

Following publication of the original article [1], the authors reported that the headers in Table 2 in their paper were omitted.
Transcriptional inhibition by CDK7/9 inhibitor SNS-032 abrogates oncogene addiction and reduces liver metastasis in uveal melanoma
Authors: Zhang Jing , Liu Shenglan , Ye Qianyun , Pan Jingxuan
Published: September 2019

Background

Life of patients with uveal melanoma (UM) is largely threatened by liver metastasis. Little is known about the drivers of liver organotropic metastasis in UM. The elevated activity of transcription of oncogenes is presumably to drive aspects of tumors. We hypothesized that inhibition of transcription by cyclin-dependent kinase 7/9 (CDK7/9) inhibitor SNS-032 diminished liver metastasis by abrogating the putative oncogenes in charge of colonization, stemness, cell motility of UM cells in host liver microenvironment.

Methods

The effects of SNS-032 on the expression of the relevant oncogenes were examined by qRT-PCR and Western blotting analysis. Proliferative activity, frequency of CSCs and liver metastasis were evaluated by using NOD-SCID mouse xenograft model and NOG mouse model, respectively.

Results

The results showed that CDK7/9 were highly expressed in UM cells, and SNS-032 significantly suppressed the cellular proliferation, induced apoptosis, and inhibited the outgrowth of xenografted UM cells and PDX tumors in NOD-SCID mice, repressed the cancer stem-like cell (CSC) properties through transcriptional inhibition of stemness-related protein Krüppel-like factor 4 (KLF4), inhibited the invasive phonotypes of UM cells through matrix metalloproteinase 9 (MMP9). Mechanistically, SNS-032 repressed the c-Myc-dependent transcription of RhoA gene, and thereby lowered the RhoA GTPase activity and actin polymerization, and subsequently inhibited cell motility and liver metastasis.

Conclusions

In conclusion, we validate a set of transcription factors which confer metastatic traits (e.g., KLF4 for CSCs, c-Myc for cell motility) in UM cells. Our results identify SNS-032 as a promising therapeutic agent, and warrant a clinical trial in patients with metastatic UM.
Correction to: Synergistic killing effects of homoharringtonine and arsenic trioxide on acute myeloid leukemia stem cells and the underlying mechanisms
Authors: Tan Ming , Zhang Qian , Yuan Xiaohong , Chen Yuanzhong , Wu Yong
Published: September 2019

In the publication of this article [1], there are two corrections.
Myceliophthora thermophila Xyr1 is predominantly involved in xylan degradation and xylose catabolism
Authors: dos Santos Gomes Ana Carolina , Falkoski Daniel , Battaglia Evy , Peng Mao , Nicolau de Almeida Maira , Coconi Linares Nancy , Meijnen Jean-Paul , Visser Jaap , de Vries Ronald P.
Published: September 2019

Background

Myceliophthora thermophila is a thermophilic ascomycete fungus that is used as a producer of enzyme cocktails used in plant biomass saccharification. Further development of this species as an industrial enzyme factory requires a detailed understanding of its regulatory systems driving the production of plant biomass-degrading enzymes. In this study, we analyzed the function of MtXlr1, an ortholog of the (hemi-)cellulolytic regulator XlnR first identified in another industrially relevant fungus, Aspergillus niger.

Results

The Mtxlr1 gene was deleted and the resulting strain was compared to the wild type using growth profiling and transcriptomics. The deletion strain was unable to grow on xylan and d-xylose, but showed only a small growth reduction on l-arabinose, and grew similar to the wild type on Avicel and cellulose. These results were supported by the transcriptome analyses which revealed reduction of genes encoding xylan-degrading enzymes, enzymes of the pentose catabolic pathway and putative pentose transporters. In contrast, no or minimal effects were observed for the expression of cellulolytic genes.

Conclusions

Myceliophthora thermophila MtXlr1 controls the expression of xylanolytic genes and genes involved in pentose transport and catabolism, but has no significant effects on the production of cellulases. It therefore resembles more the role of its ortholog in Neurospora crassa, rather than the broader role described for this regulator in A. niger and Trichoderma reesei. By revealing the range of genes controlled by MtXlr1, our results provide the basic knowledge for targeted strain improvement by overproducing or constitutively activating this regulator, to further improve the biotechnological value of M. thermophila.
Combined resistance to oxidative stress and reduced antenna size enhance light-to-biomass conversion efficiency in Chlorella vulgaris cultures
Authors: Dall’Osto Luca , Cazzaniga Stefano , Guardini Zeno , Barera Simone , Benedetti Manuel , Mannino Giuseppe , Maffei Massimo E. , Bassi Roberto
Published: September 2019

Background

Microalgae are efficient producers of lipid-rich biomass, making them a key component in developing a sustainable energy source, and an alternative to fossil fuels. Chlorella species are of special interest because of their fast growth rate in photobioreactors. However, biological constraints still cast a significant gap between the high cost of biofuel and cheap oil, thus hampering perspective of producing CO2-neutral biofuels. A key issue is the inefficient use of light caused by its uneven distribution in the culture that generates photoinhibition of the surface-exposed cells and darkening of the inner layers. Efficient biofuel production, thus, requires domestication, including traits which reduce optical density of cultures and enhance photoprotection.

Results

We applied two steps of mutagenesis and phenotypic selection to the microalga Chlorella vulgaris. First, a pale-green mutant (PG-14) was selected, with a 50% reduction of both chlorophyll content per cell and LHCII complement per PSII, with respect to WT. PG-14 showed a 30% increased photon conversion into biomass efficiency vs. WT. A second step of mutagenesis of PG-14, followed by selection for higher tolerance to Rose Bengal, led to the isolation of pale-green genotypes, exhibiting higher resistance to singlet oxygen (strains SOR). Growth in photobioreactors under high light conditions showed an enhanced biomass production of SOR strains with respect to PG-14. When compared to WT strain, biomass yield of the pale green + sor genotype was enhanced by 68%.

Conclusions

Domestication of microalgae like Chlorella vulgaris, by optimizing both light distribution and ROS resistance, yielded an enhanced carbon assimilation rate in photobioreactor.