bluuebunny/crossref_metadata_2025_split huggingface dataset:
A single proteolytic cleavage within the lower hinge of trastuzumab reduces immune effector function and in vivo efficacy
Authors: Fan Xuejun , Brezski Randall J , Fa Ming , Deng Hui , Oberholtzer Allison , Gonzalez Anneliese , Dubinsky William P , Strohl William R , Jordan Robert E , Zhang Ningyan , An Zhiqiang 
Published: August 2012

Abstract
Introduction
Recent studies reported that human IgG antibodies are susceptible to specific proteolytic cleavage in their lower hinge region, and the hinge cleavage results in a loss of Fc-mediated effector functions. Trastuzumab is a humanized IgG1 therapeutic monoclonal antibody for the treatment of HER2-overexpressing breast cancers, and its mechanisms of action consist of inhibition of HER2 signaling and Fc-mediated antibody-dependent cellular cytotoxicity (ADCC). The objective of this study is to investigate the potential effect of proteinase hinge cleavage on the efficacy of trastuzumab using both a breast cancer cell culture method and an in vivo mouse xenograft tumor model.

Methods
Trastuzumab antibody was incubated with a panel of human matrix metalloproteinases, and proteolytic cleavage in the lower hinge region was detected using both western blotting and mass spectrometry. Single hinge cleaved trastuzumab (scIgG-T) was purified and evaluated for its ability to mediate ADCC and inhibition of breast cancer cell proliferation in vitro as well as anti-tumor efficacy in the mouse xenograft tumor model. Infiltrated immune cells were detected in tumor tissues by immunohistochemistry.

Results
scIgG-T retains HER2 antigen binding activity and inhibits HER2-mediated downstream signaling and cell proliferation in vitro when compared with the intact trastuzumab. However, scIgG-T lost Fc-mediated ADCC activity in vitro, and had significantly reduced anti-tumor efficacy in a mouse xenograft tumor model. Immunohistochemistry showed reduced immune cell infiltration in tumor tissues treated with scIgG-T when compared with those treated with the intact trastuzumab, which is consistent with the decreased ADCC mediated by scIgG-T in vitro.

Conclusion
Trastuzumab can be cleaved by matrix metalloproteinases within the lower hinge. scIgG-T exhibited a significantly reduced anti-tumor efficacy in vivo due to the weakened immune effector function such as ADCC. The results suggest that the lower hinge cleavage of trastuzumab can occur in the tumor microenvironment where matrix metalloproteinases often have high levels of expression and scIgG-T might compromise its anti-tumor efficacy in the clinic. However, further studies are needed to validate these hypotheses in the clinical setting.
Risk assessment in sepsis: a new prognostication rule by APACHE II score and serum soluble urokinase plasminogen activator receptor
Authors: Giamarellos-Bourboulis Evangelos J , Norrby-Teglund Anna , Mylona Vassiliki , Savva Athina , Tsangaris Iraklis , Dimopoulou Ioanna , Mouktaroudi Maria , Raftogiannis Maria , Georgitsi Marianna , Linnér Anna , Adamis George , Antonopoulou Anastasia , Apostolidou Efterpi , Chrisofos Michael , Katsenos Chrisostomos , Koutelidakis Ioannis , Kotzampassi Katerina , Koratzanis George , Koupetori Marina , Kritselis Ioannis , Lymberopoulou Korina , Mandragos Konstantinos , Marioli Androniki , Sundén-Cullberg Jonas , Mega Anna , Prekates Athanassios , Routsi Christina , Gogos Charalambos , Treutiger Carl-Johan , Armaganidis Apostolos , Dimopoulos George 
Published: August 2012

Abstract
Introduction
Early risk assessment is the mainstay of management of patients with sepsis. APACHE II is the gold standard prognostic stratification system. A prediction rule that aimed to improve prognostication by APACHE II with the application of serum suPAR (soluble urokinase plasminogen activator receptor) is developed.

Methods
A prospective study cohort enrolled 1914 patients with sepsis including 62.2% with sepsis and 37.8% with severe sepsis/septic shock. Serum suPAR was measured in samples drawn after diagnosis by an enzyme-immunoabsorbent assay; in 367 patients sequential measurements were performed. After ROC analysis and multivariate logistic regression analysis a prediction rule for risk was developed. The rule was validated in a double-blind fashion by an independent confirmation cohort of 196 sepsis patients, predominantly severe sepsis/septic shock patients, from Sweden.

Results
Serum suPAR remained stable within survivors and non-survivors for 10 days. Regression analysis showed that APACHE II ≥17 and suPAR ≥12 ng/ml were independently associated with unfavorable outcome. Four strata of risk were identified: i) APACHE II <17 and suPAR <12 ng/ml with mortality 5.5%; ii) APACHE II < 17 and suPAR ≥12 ng/ml with mortality 17.4%; iii) APACHE II ≥ 17 and suPAR <12 ng/ml with mortality 37.4%; and iv) APACHE II ≥17 and suPAR ≥12 ng/ml with mortality 51.7%. This prediction rule was confirmed by the Swedish cohort.

Conclusions
A novel prediction rule with four levels of risk in sepsis based on APACHE II score and serum suPAR is proposed. Prognostication by this rule is confirmed by an independent cohort.
Underwater hearing in the loggerhead turtle (Caretta caretta): a comparison of behavioral and auditory evoked potential audiograms
Authors: Martin Kelly J. , Alessi Sarah C. , Gaspard Joseph C. , Tucker Anton D. , Bauer Gordon B. , Mann David A. 
Published: August 2012

SUMMARY
The purpose of this study was to compare underwater behavioral and auditory evoked potential (AEP) audiograms in a single captive adult loggerhead sea turtle (Caretta caretta). The behavioral audiogram was collected using a go/no-go response procedure and a modified staircase method of threshold determination. AEP thresholds were measured using subdermal electrodes placed beneath the frontoparietal scale, dorsal to the midbrain. Both methods showed the loggerhead sea turtle to have low frequency hearing with best sensitivity between 100 and 400 Hz. AEP testing yielded thresholds from 100 to 1131 Hz with best sensitivity at 200 and 400 Hz (110 dB re. 1 μPa). Behavioral testing using 2 s tonal stimuli yielded underwater thresholds from 50 to 800 Hz with best sensitivity at 100 Hz (98 dB re. 1 μPa). Behavioral thresholds averaged 8 dB lower than AEP thresholds from 100 to 400 Hz and 5 dB higher at 800 Hz. The results suggest that AEP testing can be a good alternative to measuring a behavioral audiogram with wild or untrained marine turtles and when time is a crucial factor.
Glycogen, not dehydration or lipids, limits winter survival of side-blotched lizards (Uta stansburiana)
Authors: Zani Peter A. , Irwin Jason T. , Rollyson Mary E. , Counihan Jessica L. , Healas Sara D. , Lloyd Emily K. , Kojanis Lee C. , Fried Bernard , Sherma Joseph 
Published: August 2012

SUMMARYClimate change is causing winters to become milder (less cold and shorter). Recent studies of overwintering ectotherms have suggested that warmer winters increase metabolism and decrease winter survival and subsequent fecundity. Energetic constraints (insufficient energy stores) have been hypothesized as the cause of winter mortality but have not been tested explicitly. Thus, alternative sources of mortality, such as winter dehydration, cannot be ruled out. By employing an experimental design that compared the energetics and water content of lizards that died naturally during laboratory winter with those that survived up to the same point but were then sacrificed, we attempt to distinguish among multiple possible causes of mortality. We test the hypothesis that mortality is caused by insufficient energy stores in the liver, abdominal fat bodies, tail or carcass or through excessive water loss. We found that lizards that died naturally had marginally greater mass loss, lower water content, and less liver glycogen remaining than living animals sampled at the same time. Periodically moistening air during winter reduced water loss, but this did not affect survival, calling into question dehydration as a cause of death. Rather, our results implicate energy limitations in the form of liver glycogen, but not lipids, as the primary cause of mortality in overwintering lizards. When viewed through a lens of changing climates, our results suggest that if milder winters increase the metabolic rate of overwintering ectotherms, individuals may experience greater energetic demands. Increased energy use during winter may subsequently limit individual survival and possibly even impact population persistence.
Serotonin-induced brain glycogenolysis in rainbow trout (Oncorhynchus mykiss)
Authors: Pérez-Maceira Jorge J. , Mancebo María J. , Aldegunde Manuel 
Published: August 2012

SUMMARY
In this study, we evaluated the serotonin-mediated control of cerebral glycogen levels in the rainbow trout, Oncorhynchus mykiss. Intracerebroventricular (i.c.v.) administration of serotonin (5-HT) to normoglycemic trout (time and dose response) decreased glycogen levels in the brain and increased brain glycogen phosphorylase activity (time response). In hypoglycemic fish (that had been fasted for 5 and 10 days), there was a time-dependent decrease in brain glycogen levels; under these conditions, i.c.v. administration of 5-HT also reduced the brain glycogen content in fish that had been fasted for 5 days. In fish with local cerebral hypoglycemia (induced by 2-DG administration), the glycogen levels decreased and, as above, i.c.v. administration of 5-HT also lowered the glycogen content. In hyperglycemic fish, 5-HT did not affect glycogen levels. Administration of receptor agonists 5-HT1A (8-OH-DPAT), 5-HT1B (anpirtoline and CP93129) or 5-HT2 (α-m-5-HT) decreased the brain glycogen levels. This effect was antagonized by the administration of receptor antagonists 5-HT1A (WAY100135 and NAN190), 5-HT1B (NAS181) and 5-HT2B/C (SB206553). Administration of the receptor agonists (±)-DOI (5-HT2A/2C), m-CPP (5-HT2B/2C), BW723C86 (5-HT2B) and WAY 161503 (5-HT2C) led to decreases in the levels of brain glycogen. We found that 5-HT is involved in the modulation of brain glycogen homeostasis in the rainbow trout, causing a glycogenolytic effect when fish are in a normoglycemic or hypoglycemic state, but not when they are in a hyperglycemic state. 5-HT1A, 5-HT1B, 5HT2B and 5-HT2C-like receptors appeared to be involved in the glycogenolytic action of 5-HT, although the effect mediated by 5-HT1A or 5-HT1B was apparently stronger.
Bilateral coordination and the motor basis of female preference for sexual signals in canary song
Authors: Suthers Roderick A. , Vallet Eric , Kreutzer Michel 
Published: August 2012

SUMMARY
The preference of female songbirds for particular traits in the songs of courting males has received considerable attention, but the relationship of preferred traits to male quality is poorly understood. Female domestic canaries (Serinus canaria, Linnaeus) preferentially solicit copulation with males that sing special high repetition rate, wide-band, multi-note syllables, called ‘sexy’ or A-syllables. Syllables are separated by minibreaths but each note is produced by pulsatile expiration, allowing high repetition rates and long duration phrases. The wide bandwidth is achieved by including two notes produced sequentially on opposite sides of the syrinx, in which the left and right sides are specialized for low or high frequencies, respectively. The emphasis of low frequencies is facilitated by a positive relationship between syllable repetition rate and the bandwidth of the fundamental frequency of notes sung by the left syrinx, such that bandwidth increases with increasing syllable repetition rate. The temporal offset between notes prevents cheating by unilaterally singing a note on the left side with a low fundamental frequency and prominent higher harmonics. The syringeal and respiratory motor patterns by which sexy syllables are produced support the hypothesis that these syllables provide a sensitive vocal–auditory indicator of a male's performance limit for the rapid, precisely coordinated interhemispheric switching, which is essential for many sensory and motor processes involving specialized contributions from each cerebral hemisphere.
Evolution of high duty cycle echolocation in bats
Authors: Fenton M. Brock , Faure Paul A. , Ratcliffe John M. 
Published: August 2012

SummaryDuty cycle describes the relative ‘on time’ of a periodic signal. In bats, we argue that high duty cycle (HDC) echolocation was selected for and evolved from low duty cycle (LDC) echolocation because increasing call duty cycle enhanced the ability of echolocating bats to detect, lock onto and track fluttering insects. Most echolocators (most bats and all birds and odontocete cetaceans) use LDC echolocation, separating pulse and echo in time to avoid forward masking. They emit short duration, broadband, downward frequency modulated (FM) signals separated by relatively long periods of silence. In contrast, bats using HDC echolocation emit long duration, narrowband calls dominated by a single constant frequency (CF) separated by relatively short periods of silence. HDC bats separate pulse and echo in frequency by exploiting information contained in Doppler-shifted echoes arising from their movements relative to background objects and their prey. HDC echolocators are particularly sensitive to amplitude and frequency glints generated by the wings of fluttering insects. We hypothesize that narrowband/CF calls produced at high duty cycle, and combined with neurobiological specializations for processing Doppler-shifted echoes, were essential to the evolution of HDC echolocation because they allowed bats to detect, lock onto and track fluttering targets. This advantage was especially important in habitats with dense vegetation that produce overlapping, time-smeared echoes (i.e. background acoustic clutter). We make four specific, testable predictions arising from this hypothesis.
Medication Use and Associated Risk of Falling in a Geriatric Outpatient Population
Authors: Freeland Kathryn N , Thompson Amy N , Zhao Yumin , Leal Julie E , Mauldin Patrick D , Moran William P 
Published: August 2012

BACKGROUND: Studies have shown that approximately one third of community-dwelling people aged 65 years and older will experience a fall each year. Many studies indicate that use of multiple medications may put patients at an increased risk of falling, but few studies have been conducted to correlate the number of medications with the risk of falls. OBJECTIVE: To determine the medications most frequently used in patients aged 65 years or older who have experienced a fall within the past year, with particular attention to type or number of medications most commonly associated with multiple falls or a fall with injury. METHODS: We conducted a chart review in an outpatient internal medicine clinic over a 13-month period. A total of 118 patients 65 years of age or older who were taking 4 or more medications and had experienced at least 1 fall in the previous 12 months were included. Data relating to sex, age, race, diagnoses, medications, and number and type of falls were obtained during the chart review. The primary end point of the study was number and type of medications most commonly used in patients experiencing a fall. RESULTS: A total of 116 patients were examined for trends in fall risk. A logistic regression model and receiver operating characteristic curve demonstrated significant fall risk with the addition of medications, with patients experiencing a 14% increase in fall risk with the addition of each medication beyond a 4-medication regimen (OR 1.14; 95% CI 1.02 to 1.27; p = 0.027). CONCLUSIONS: The addition of medications is associated with a significant increase in risk of falls in elderly patients, regardless of drug class. Further studies are needed to assess the possible increased risk of falls with increasing number of medications.
Organization of Cerebral Projections to Identified Cerebellar Zones in the Posterior Cerebellum of the Rat
Authors: Suzuki Lucia , Coulon Patrice , Sabel-Goedknegt Erika H. , Ruigrok Tom J. H. 
Published: August 2012

The cerebrocerebellar connection makes use of two of the largest fiber tracts in the mammalian brain, i.e., the cerebral and medial cerebellar peduncles. Neuroanatomical approaches aimed to elucidate the organization of this important connection have been hindered by its multisynaptic nature, the complex organization of its components, and the dependency of conventional tracers on precisely placed injections. To overcome these problems, we used rabies virus (RV) as a retrograde transneuronal tracer. RV was injected simultaneously with cholera toxin β subunit (CTb) into selected areas of the cerebellar cortex of 18 male Wistar rats. A survival time of 48–50 h resulted in first- and second-order labeling of RV in combination with first-order labeling of CTb. The distribution of CTb-labeled neurons in the inferior olive established the zonal identity of the injection site. In this way, it was possible to examine the cortical distribution of neurons from which disynaptic cerebrocerebellar projections to specific cerebellar loci originate.The results show that this distribution covaries with the identity of the injected cerebellar lobule. More subtle changes were present when different zones of the same lobule were injected. The C1 zone of lobule VIII receives a more prominent projection from the somatosensory cortex compared with the C2/D zones. The laterally positioned D zones receive information from more rostral regions of the cerebral cortex. The vermis of lobule VII receives a prominent input from the retrosplenial and orbitofrontal cortices. Different injection sites also result in differences in laterality of the connections.
Die Magische Dimension: Be-Greifbare Interaktion auf und über Tabletops
Authors: Spindler Martin , Dachselt Raimund 
Published: August 2012

Zusammenfassung
Aktuelle technische Entwicklungen am Smartphone- und Tablet-Markt zeigen, dass die Verschmelzung von Eingabe und Ausgabe im selben Gerät zu einer direkteren und als natürlicher empfundenen Interaktion führt. Während sich ein Grossteil bisheriger Forschung der Entwicklung von Touchtechniken auf derartigen berührungsempfindlichen Displays widmet, lösen wir uns von den Beschränkungen einer interaktiven Oberfläche und erweitern den Interaktionsraum auf den physischen dreidimensionalen (3D) Raum oberhalb eines Tabletops. Mit lagebewussten, in der Hand gehaltenen Papierdisplays stellen wir einen vielversprechenden Ansatz vor, der diesen Raum nutzt. Durch die zusätzliche Verwendung der Position und Orientierung dieser Papierdisplays (be-greifbare Linsen) mit unterschiedlicher Form und Grösse können Nutzer eine sehr direkte, greifbare Interaktion mit verschiedenen Informationsräumen erleben. Der gleichzeitige Einsatz multipler Linsen unterstützt kollaboratives Arbeiten explizit. Der Artikel stellt neben grundlegenden Interaktionskonzepten auf und mit den Linsen auch konkrete Anwendungsfälle vor, diskutiert die Vor- und Nachteile aktiver und passiver Displays und erläutert den technischen Aufbau des Systems.
Be-greifbare Interaktionen mit grössenveränderbaren Bildschirmen
Authors: Steimle Jürgen , Lissermann Roman , Olberding Simon , Khalilbeigi Mohammadreza , Kleine Wolfgang , Mühlhäuser Max 
Published: August 2012

Zusammenfassung
Neue Technologien für flexible Bildschirme ermöglichen Bildschirme, die physisch verformbar sind. Dies eröffnet das Potenzial, Bildschirme und deren Inhalte auf neue Art be-greifbar zu machen. In diesem Artikel untersuchen wir, wie Nutzer mit Inhalten auf Bildschirmen interagieren können, die durch Rollen oder Falten in ihrer Grösse verändert werden können. Dies ist insbesondere im Kontext von mobilen Endgeräten relevant, deren Nutzbarkeit durch grössen-veränderbare Bildschirme deutlich verbessert werden kann. Wir führen diese neue Klasse be-greifbarer Interaktionen ein, identifizieren grundsätzliche Funktionen der Grössenveränderung und stellen diese anhand von Beispielanwendungen vor.
Was erwarten Usability Experten von Anforderungsdokumenten?
Authors: Gross Anne , Hess Steffen 
Published: August 2012

Zusammenfassung
Die Erreichbarkeit einer hohen Usability sowie User Experience in Softwareprodukten setzt ein detailliertes Verständnis über Benutzer und deren Aufgaben voraus. Daher bilden Anforderungsdokumente für die Aktivitäten von Usability Experten eine wichtige Arbeitsgrundlage. Aber auch für die Aufgaben anderer Rollen wie Softwarearchitekten und Tester bilden diese Dokumente eine wichtige Informationsquelle. Dies bringt jedoch die Herausforderung mit sich, dass in Anforderungsdokumenten unterschiedliche Informationsbedarfe adressiert werden müssen, was deren Nutzbarkeit für die einzelnen Rollen negativ beeinflusst. Um geeignete Lösungen für dieses Problem zu entwickeln, ist empirisch fundiertes Wissen über Informationsbedarfe eine unabdingbare Voraussetzung. In diesem Beitrag werden Aufbau und Ergebnisse erster Studien vorgestellt, welche Informationsbedarfe an Anforderungsdokumente aus Sicht von Usability Experten untersucht haben. Dabei konnten erste Erkenntnisse hinsichtlich der Relevanz von Artefakten wie Beschreibungen von Endnutzern und Interaktionen gewonnen werden. Unterschiede innerhalb der Teilnehmergruppe, insbesondere im Hinblick auf den Detaillierungsgrad der relevanten Artefakte erfordern weitere Studien, welche Einflussfaktoren auf Informationsbedarfe genauer untersuchen.
Soft‐Tissue Alterations Following Exposure to Tooth‐Whitening Agents
Authors: Lucier Rebekah N. , Etienne Olivier , Ferreira Susana , Garlick Jonathan A. , Kugel Gerard , Egles Christophe 
Published: August 2012

Background: Tooth‐whitening agents are widely used, either as self‐application products or under the supervision of a dentist. These products may be associated with transient gross morphologic changes in oral soft tissues. However, their potential effects on human keratinocytes and fibroblasts in a stratified squamous epithelium have yet to be elucidated.Methods: In this study, three‐dimensional human tissue equivalents are exposed to varying concentrations of tooth‐whitening agents for increasing time periods. Tissue alterations are investigated in terms of morphology, proliferation, apoptosis, and protein expression.Results: All whitening agents tested altered tissue morphology, induced proliferation of basal keratinocytes, and caused apoptosis of cells in all epithelial strata. In addition, whitening agents induced alterations in the expression of cytokines that are linked to inflammation.Conclusions: These results suggest that whitening agents may induce similar changes in vivo and that these products should be used for limited periods of time or under the supervision of a dental professional.
The Association between Audit Committee Multiple-Directorships, Tenure, and Financial Misstatements
Authors: Sharma Vineeta D. , Iselin Errol R. 
Published: August 2012

SUMMARY
This study examines the association between multiple-directorships and tenure of independent audit committee members and financial misstatements in the pre- and post-Sarbanes-Oxley (SOX) reform environment. Regulatory reforms following the accounting scandals at Enron and WorldCom substantially expanded the responsibilities and scrutiny of the audit committee and, consequently, amplify the reputational and litigation risks facing the directors serving on the committee. Our results show a significant positive association between financial misstatements and multiple-directorships in the post-SOX environment. This finding suggests that independent audit committee members serving on multiple boards may be stretched too thinly to effectively perform their monitoring responsibilities. We also find a significant positive association between the tenure of independent audit committee members and financial misstatements in the post-SOX environment, suggesting that directors with longer tenure may not exercise independent judgment. These observations support calls for limits on multiple-directorships and director tenure, and add to our understanding of how independent directors' characteristics affect the effectiveness of the audit committee.