bluuebunny/crossref_metadata_2025 huggingface dataset:
Corynebacterium accolens Releases Antipneumococcal Free Fatty Acids from Human Nostril and Skin Surface Triacylglycerols
Authors: Bomar Lindsey , Brugger Silvio D. , Yost Brian H. , Davies Sean S. , Lemon Katherine P.
Published: January 2016

Bacterial interspecies interactions play clinically important roles in shaping microbial community composition. We observed that
Corynebacterium
spp. are overrepresented in children free of
Streptococcus pneumoniae
(pneumococcus), a common pediatric nasal colonizer and an important infectious agent.
Corynebacterium accolens
, a benign lipid-requiring species, inhibits pneumococcal growth during
in vitro
cocultivation on medium supplemented with human skin surface triacylglycerols (TAGs) that are likely present in the nostrils. This inhibition depends on LipS1, a TAG lipase necessary for
C. accolens
growth on TAGs such as triolein. We determined that
C. accolens
hydrolysis of triolein releases oleic acid, which inhibits pneumococcus, as do other free fatty acids (FFAs) that might be released by LipS1 from human skin surface TAGs. Our results support a model in which
C. accolens
hydrolyzes skin surface TAGS
in vivo
releasing antipneumococcal FFAs. These data indicate that
C. accolens
may play a beneficial role in sculpting the human microbiome.

IMPORTANCE
Little is known about how harmless
Corynebacterium
species that colonize the human nose and skin might impact pathogen colonization and proliferation at these sites
.
We show that
Corynebacterium accolens
, a common benign nasal bacterium, modifies its local habitat
in vitro
as it inhibits growth of
Streptococcus pneumoniae
by releasing antibacterial free fatty acids from host skin surface triacylglycerols. We further identify the primary
C. accolens
lipase required for this activity. We postulate a model in which higher numbers of
C. accolens
cells deter/limit
S. pneumoniae
nostril colonization, which might partly explain why children without
S. pneumoniae
colonization have higher levels of nasal
Corynebacterium
. This work narrows the gap between descriptive studies and the needed in-depth understanding of the molecular mechanisms of microbe-microbe interactions that help shape the human microbiome. It also lays the foundation for future
in vivo
studies to determine whether habitat modification by
C. accolens
could be promoted to control pathogen colonization.
Bronchiolitis obliterans organising pneumonia associated with anticonvulsant hypersensitivity syndrome induced by lamotrigine
Authors: Ghandourah Hasan , Bhandal Samarjeet , Brundler Marie-Anne , Noseworthy Mary
Published: January 2016

A 14-year-old girl who was known to have a seizure disorder and on lamotrigine treatment was admitted to the hospital, with a history of rash, fever and cough. Her condition deteriorated with clinical features suggestive of anticonvulsant hypersensitivity syndrome (ACHS) complicated with bronchiolitis obliterans organising pneumonia (BOOP). Her chest CT showed multifocal parenchymal opacities and lung biopsy was typical for BOOP. Initially, the lamotrigine was discontinued since the onset of the rash, then she was treated for pneumonia with antibiotics, which may have delayed the diagnosis. Eventually, BOOP was considered and she was treated with a high dose of corticosteroid. She improved clinically and her repeated chest CT showed a marked resolution of the lesions. This case illustrates the possible occurrence of BOOP as a complication of ACHS secondary to lamotrigine treatment.
Management of hyper-flexion injury-related teardrop fracture in an adolescent
Authors: Maharaj Monish , Phan Kevin , Mobbs Ralph J
Published: January 2016

We present a case of a flexion teardrop fracture managed surgically with anterior stabilisation and fusion between the affected vertebral body to its posteriorly adjacent level. A 14-year-old girl presented with severe neck pain following a fall from a bunk bed. MRI investigation showed signs of axial loading and hyper-flexion yielding a teardrop fracture at the body of the C5 vertebra. Using a novel technique, the patient was treated surgically with an anterior fusion of the C5-C6 vertebra. Her 12-month follow-up demonstrated full functional ability.
Financial accessibility and user fee reforms for maternal healthcare in five sub-Saharan countries: a quasi-experimental analysis
Authors: Leone Tiziana , Cetorelli Valeria , Neal Sarah , Matthews Zoë
Published: January 2016

Objectives

Evidence on whether removing fees benefits the poorest is patchy and weak. The aim of this paper is to measure the impact of user fee reforms on the probability of giving birth in an institution or undergoing a caesarean section (CS) in Ghana, Burkina Faso, Zambia, Cameroon and Nigeria for the poorest strata of the population.

Setting

Women's experience of user fees in 5 African countries.

Primary and secondary outcome measures

Using quasi-experimental regression analysis we tested the impact of user fee reforms on facilities’ births and CS differentiated by wealth, education and residence in Burkina Faso and Ghana. Mapping of the literature followed by key informant interviews are used to verify details of reform implementation and to confirm and support our countries’ choice.

Participants

We analysed data from consecutive surveys in 5 countries: 2 case countries that experienced reforms (Ghana and Burkina Faso) by contrast with 3 that did not experience reforms (Zambia, Cameroon, Nigeria).

Results

User fee reforms are associated with a significant percentage of the increase in access to facility births (27 percentage points) and to a much lesser extent to CS (0.7 percentage points). Poor (but not the poorest), and non-educated women, and those in rural areas benefitted the most from the reforms. User fees reforms have had a higher impact in Burkina Faso compared with Ghana.

Conclusions

Findings show a clear positive impact on access when user fees are removed, but limited evidence for improved availability of CS for those most in need. More women from rural areas and from lower socioeconomic backgrounds give birth in health facilities after fee reform. Speed and quality of implementation might be the key reason behind the differences between the 2 case countries. This calls for more research into the impact of reforms on quality of care.
Effectiveness, safety and costs of thromboembolic prevention in patients with non-valvular atrial fibrillation: phase I ESC-FA protocol study and baseline characteristics of a cohort from a primary care electronic database
Authors: Giner-Soriano Maria , Vedia Urgell Cristina , Roso-Llorach Albert , Morros Rosa , Capellà Dolors , Castells Xavier , Ferreira-González Ignacio , Troncoso Mariño Amelia , Diògene Eduard , Elorza Josep Mª , Casajuana Marc , Bolíbar Bonaventura , Violan Concepció
Published: January 2016

Purpose

Atrial fibrillation is the most common arrhythmia. Its management aims to reduce symptoms and to prevent complications through rate and rhythm control, management of concomitant cardiac diseases and prevention of related complications, mainly stroke. The main objective of Effectiveness, Safety and Costs in Atrial Fibrillation (ESC-FA) study is to analyse the drugs used for the management of the disease in real-use conditions, particularly the antithrombotic agents for stroke prevention. The aim of this work is to present the study protocol of phase I of the ESC-FA study and the baseline characteristics of newly diagnosed patients with atrial fibrillation in Catalonia, Spain.

Participants

The data source is System for the Improvement of Research in Primary Care (SIDIAP) database. The population included are all patients with non-valvular atrial fibrillation diagnosis registered in the electronic health records during 2007–2012.

Findings to date

A total of 22 585 patients with non-valvular atrial fibrillation were included in the baseline description. Their mean age was 72.8 years and 51.6% were men. The most commonly prescribed antithrombotics were vitamin K antagonists (40.1% of patients) and platelet aggregation inhibitors (32.9%); 25.3% had not been prescribed antithrombotic treatment. Age, gender, comorbidities and co-medication at baseline were similar to those reported for previous studies.

Future plans

The next phase in the ESC-FA study will involve assessing the effectiveness and safety of antithrombotic treatments, analysing stroke events and bleeding episodes’ rates in our patients (rest of phase I), describing the current management of the disease and its costs in our setting, and assessing how the introduction of new oral anticoagulants changes the stroke prevention in non-valvular atrial fibrillation.
ChineseObstetrics & Gynecologyjournal club: a randomised controlled trial
Authors: Tsui Ilene K , Dodson William C , Kunselman Allen R , Kuang Hongying , Han Feng-Juan , Legro Richard S , Wu Xiao-Ke
Published: January 2016

Objectives

To assess whether a journal club model could improve comprehension and written and spoken medical English in a population of Chinese medical professionals.

Setting and participants

The study population consisted of 52 medical professionals who were residents or postgraduate master or PhD students in the Department of Obstetrics and Gynecology, Heilongjiang University of Chinese Medicine, China.

Intervention

After a three-part baseline examination to assess medical English comprehension, participants were randomised to either (1) an intensive journal club treatment arm or (2) a self-study group. At the conclusion of the 8-week intervention participants (n=52) were re-tested with new questions.

Outcome measures

The primary outcome was the change in score on a multiple choice examination. Secondary outcomes included change in scores on written and oral examinations which were modelled on the Test of English as a Foreign Language (TOEFL).

Results

Both groups had improved scores on the multiple choice examination without a statistically significant difference between them (90% power). However, there was a statistically significant difference between the groups in mean improvement in scores for both written (95% CI 1.1 to 5.0; p=0.003) and spoken English (95% CI 0.06 to 3.7; p=0.04) favouring the journal club intervention.

Conclusions

Interacting with colleagues and an English-speaking facilitator in a journal club improved both written and spoken medical English in Chinese medical professionals. Journal clubs may be suitable for use as a self-sustainable teaching model to improve fluency in medical English in foreign medical professionals.

Trial registration number

NCT01844609.
Effect of temperature on the shear strength of soils and the soil–structure interface
Authors: Yavari Neda , Tang Anh Minh , Pereira Jean-Michel , Hassen Ghazi
Published: January 2016

In the present work, the shear behaviour of soils and the soil–concrete interface is investigated through direct shear tests at various temperatures. A conventional direct shear apparatus, equipped with a temperature control system, was used to test sand, clay, and the clay–concrete interface at various temperatures (5, 20, and 40 °C). These values correspond to the range of temperatures observed near thermoactive geostructures. Tests were performed at normal stress values ranging from 5 to 80 kPa. Results show that the effect of temperature on the shear strength parameters of soils and the soil–concrete interface is negligible. A softening behaviour was observed during shearing of the clay–concrete interface, which was not the case with clay specimens. The peak strength of the clay–concrete interface is smaller than the ultimate shear strength of clay.
Further studies on the focal mechanism and source rupture process of the 2012 Haida Gwaii, Canada, 7.8 moment magnitude earthquake
Authors: Motazedian Dariush , Zhang Yong , Ma Shutian , Chen Yun-tai
Published: January 2016

The 28 October 2012 Haida Gwaii, British Columbia, Canada, earthquake with a moment magnitude (MW) of 7.8 occurred along an east-dipping poorly known thrust fault beneath the Queen Charlotte Terrace. It was the largest thrust event ever recorded in this dominated by strike-slip motion region. We studied the focal mechanism and the source rupture process for the event. The retrieved geometric parameters of the fault plane were a strike of 329°, dip of 24°, and slip of 114°. The isotropic moment was negative, and its value was about one-fifth of the total seismic moment released. The earthquake ruptured an area of about 160 km × 60 km, and major slip occurred in an area of about 100 km × 60 km. The maximum slip was about 5.8 m. The slip distribution on the fault plane was highly heterogeneous, with four slip patches. The main slip lay on a large zone above the hypocentre to the sea floor. The maximum and average stress drops calculated using the Brune model were 16.5 and 4.6 MPa, respectively. The major rupture occurred about 10 s after the rupture initiation, and lasted about 25 s. During a subducting earthquake, the leading edge of the overriding plate is assumed to spring seaward and upward, while the landward portion is assumed to extend and drop down, and the generated rapid motions set off a tsunami. The falling-down process seems to be consistent with a negative isotropic moment.
Geochemical processes in the formation of ‘forest rings’: examples of reduced chimney formation in the absence of mineral deposits
Authors: Brauneder Kerstin , Hamilton Stewart M. , Hattori Keiko
Published: January 2016

Forest rings are large circular features common in boreal forests in Ontario, Canada, characterized by ring-shaped topographic depressions in carbonate-rich soil. This paper documents the compositional variation of soil and of the peat that commonly fills the depression, along transects across two representative rings: one centred on an accumulation of CH
4
in glacial sediments and the other on H
2
S in both glacial sediments and bedrock. Clayey mineral soil at the ring edge (annulus) shows low pH, oxidation-reduction potential (ORP), Ca and carbonate, and high Al, Fe and Mn by both
aqua regia
digestion and a 0.25M hydroxylamine hydrochloride leach (0.25M NH
2
OH.HCl at 60
°
C). Antithetic responses occur in the overlying peat, including elevated carbonate and pH over the areas with low pH, ORP and carbonate in the mineral soil. The observed relationships suggest vertical migration of carbonate species from mineral soil into peat at the annulus, and lateral migration from the annulus to adjacent areas in the mineral soil. The geochemical data support the hypothesis that forest rings are the surface expression of reduced chimneys, similar to those observed over metallic mineral deposits, despite both these sites being known to be barren. Strongly negative ORP values in shallow soils in the annulus suggest autotrophic microbiological activity contributes to the sharp change in redox conditions at the ring boundaries. The similar geochemical responses at forest rings and soils over mineral deposits show that these features can be used to understand the variation in redox, pH, metals and soil hydrocarbons over mineral deposits and to help differentiate ore-related from secondary geochemical features due to the presence of a reduced chimney.
Effect of type II diabetes on male rat bladder contractility
Authors: Kendig Derek M. , Ets Hillevi K. , Moreland Robert S.
Published: January 2016

Type II diabetes is the most prevalent form of diabetes. One of the primary complications of diabetes that significantly affects quality of life is bladder dysfunction. Many studies on diabetic bladder dysfunction have been performed in models of type I diabetes; however, few have been performed in animal models of type II diabetes. Using the Zucker Diabetic Fatty (ZDF) rat model of type II diabetes, we examined the contractility and sensitivity of bladder smooth muscle in response to mediators of depolarization-induced contraction, muscarinic receptor-mediated contraction, ATP-induced contraction, and neurogenic contraction. Studies were performed at 16 and 27 wk of age to monitor the progression of diabetic bladder dysfunction. Voiding behavior was also quantified. The entire bladder walls of diabetic rats were hypertrophied compared with that of control rats. Contractility and sensitivity to carbachol and ATP were increased at 27 wk in bladder smooth muscle strips from diabetic rats, suggesting a compensated state of diabetic bladder dysfunction. Purinergic signaling was increased in response to exogenous ATP in bladders from diabetic animals; however, the purinergic component of neurogenic contractions was decreased. The purinergic component of neurogenic contraction was reduced by P2X receptor desensitization, but was unchanged by P2X receptor inhibition in diabetic rats. Residual and tetrodotoxin-resistant components of neurogenic contraction were increased in bladder strips from diabetic animals. Overall, our results suggest that in the male ZDF rat model, the bladder reaches the compensated stage of function by 27 wk and has increased responsiveness to ATP.
Intercostal muscle motor behavior during tracheal occlusion conditioning in conscious rats
Authors: Jaiswal Poonam B. , Davenport Paul W.
Published: January 2016

A respiratory load compensation response is characterized by increases in activation of primary respiratory muscles and/or recruitment of accessory respiratory muscles. The contribution of the external intercostal (EI) muscles, which are a primary respiratory muscle group, during normal and loaded breathing remains poorly understood in conscious animals. Consciousness has a significant role on modulation of respiratory activity, as it is required for the integration of behavioral respiratory responses and voluntary control of breathing. Studies of respiratory load compensation have been predominantly focused in anesthetized animals, which make their comparison to conscious load compensation responses challenging. Using our established model of intrinsic transient tracheal occlusions (ITTO), our aim was to evaluate the motor behavior of EI muscles during normal and loaded breathing in conscious rats. We hypothesized that 1) conscious rats exposed to ITTO will recruit the EI muscles with an increased electromyogram (EMG) activation and 2) repeated ITTO for 10 days would potentiate the baseline EMG activity of this muscle in conscious rats. Our results demonstrate that conscious rats exposed to ITTO respond by recruiting the EI muscle with a significantly increased EMG activation. This response to occlusion remained consistent over the 10-day experimental period with little or no effect of repeated ITTO exposure on the baseline ∫EI EMG amplitude activity. The pattern of activation of the EI muscle in response to an ITTO is discussed in detail. The results from the present study demonstrate the importance of EI muscles during unloaded breathing and respiratory load compensation in conscious rats.
Relationship of brown adipose tissue perfusion and function: a study through β2-adrenoreceptor stimulation
Authors: Ernande Laura , Stanford Kristin I. , Thoonen Robrecht , Zhang Haihua , Clerte Maëva , Hirshman Michael F. , Goodyear Laurie J. , Bloch Kenneth D. , Buys Emmanuel S. , Scherrer-Crosbie Marielle
Published: January 2016

Brown adipose tissue (BAT) activation increases glucose and lipid consumption; as such, it is been considered as a potential therapy to decrease obesity. BAT is highly vascularized and its activation is associated with a necessary increase in blood flow. However, whether increasing BAT blood flow per se increases BAT activity is unknown. To examine this hypothesis, we investigated whether an isolated increase in BAT blood flow obtained by β2-adrenoreceptor (β2-AR) stimulation with salbutamol increased BAT activity. BAT blood flow was estimated in vivo in mice using contrast-enhanced ultrasound. The absence of direct effect of salbutamol on the function of isolated brown adipocytes was assessed by measuring oxygen consumption. The effect of salbutamol on BAT activity was investigated by measuring BAT glucose uptake in vivo. BAT blood flow increased by 2.3 ± 0.6-fold during β2-AR stimulation using salbutamol infusion in mice ( P = 0.003). β2-AR gene expression was detectable in BAT but was extremely low in isolated brown adipocytes. Oxygen consumption of isolated brown adipocytes did not change with salbutamol exposure, confirming the absence of a direct effect of β2-AR agonist on brown adipocytes. Finally, β2-AR stimulation by salbutamol increased BAT glucose uptake in vivo (991 ± 358 vs. 135 ± 49 ng glucose/mg tissue/45 min in salbutamol vs. saline injected mice, respectively, P = 0.046). In conclusion, an increase in BAT blood flow without direct stimulation of the brown adipocytes is associated with increased BAT metabolic activity. Increasing BAT blood flow might represent a new therapeutic target in obesity.
Immediate manifestation of acoustic trauma in the auditory cortex is layer specific and cell type dependent
Authors: Novák Ondřej , Zelenka Ondřej , Hromádka Tomáš , Syka Josef
Published: January 2016

Exposure to loud sounds damages the auditory periphery and induces maladaptive changes in central parts of the auditory system. Diminished peripheral afferentation and altered inhibition influence the processing of sounds in the auditory cortex. It is unclear, however, which types of inhibitory interneurons are affected by acoustic trauma. Here we used single-unit electrophysiological recording and two-photon calcium imaging in anesthetized mice to evaluate the effects of acute acoustic trauma (125 dB SPL, white noise, 5 min) on the response properties of neurons in the core auditory cortex. Electrophysiological measurements suggested the selective impact of acoustic trauma on inhibitory interneurons in the auditory cortex. To further investigate which interneuronal types were affected, we used two-photon calcium imaging to record the activity of neurons in cortical layers 2/3 and 4, specifically focusing on parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons. Spontaneous and pure-tone-evoked firing rates of SST+ interneurons increased in layer 4 immediately after acoustic trauma and remained almost unchanged in layer 2/3. Furthermore, PV+ interneurons with high best frequencies increased their evoked-to-spontaneous firing rate ratios only in layer 2/3 and did not change in layer 4. Finally, acoustic trauma unmasked low-frequency excitatory inputs only in layer 2/3. Our results demonstrate layer-specific changes in the activity of auditory cortical inhibitory interneurons within minutes after acoustic trauma.
Properties and physiological function of Ca2+-dependent K+currents in uniglomerular olfactory projection neurons
Authors: Bradler Cathleen , Warren Ben , Bardos Viktor , Schleicher Sabine , Klein Andreas , Kloppenburg Peter
Published: January 2016

Ca2+-activated potassium currents [ IK(Ca)] are an important link between the intracellular signaling system and the membrane potential, which shapes intrinsic electrophysiological properties. To better understand the ionic mechanisms that mediate intrinsic firing properties of olfactory uniglomerular projection neurons (uPNs), we used whole cell patch-clamp recordings in an intact adult brain preparation of the male cockroach Periplaneta americana to analyze IK(Ca). In the insect brain, uPNs form the principal pathway from the antennal lobe to the protocerebrum, where centers for multimodal sensory processing and learning are located. In uPNs the activation of IK(Ca)was clearly voltage and Ca2+dependent. Thus under physiological conditions IK(Ca)is strongly dependent on Ca2+influx kinetics and on the membrane potential. The biophysical characterization suggests that IK(Ca)is generated by big-conductance (BK) channels. A small-conductance (SK) channel-generated current could not be detected. IK(Ca)was sensitive to charybdotoxin (CTX) and iberiotoxin (IbTX) but not to apamin. The functional role of IK(Ca)was analyzed in occlusion experiments under current clamp, in which portions of IK(Ca)were blocked by CTX or IbTX. Blockade of IK(Ca)showed that IK(Ca)contributes significantly to intrinsic electrophysiological properties such as the action potential waveform and membrane excitability.
Activation of the Constitutive Androstane Receptor Increases the Therapeutic Index of CHOP in Lymphoma Treatment
Authors: Hedrich William D. , Xiao Jingwei , Heyward Scott , Zhang Yao , Zhang Junran , Baer Maria R. , Hassan Hazem E. , Wang Hongbing
Published: January 2016

The constitutive androstane receptor (CAR and NR1i3) is a key regulator of CYP2B6, the enzyme predominantly responsible for the biotransformation of cyclophosphamide (CPA) to its pharmacologically active metabolite, 4-hydroxycyclophosphamide (4-OH-CPA). Previous studies from our laboratory illustrated that CAR activation increases the formation of 4-OH-CPA; however, CPA is rarely used clinically outside of combination therapies. Here, we hypothesize that including a selective human CAR activator with the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen can improve the efficacy without exacerbating off-target toxicity of this regimen in non-Hodgkin lymphoma treatment. In this study, we have developed a novel multiorgan coculture system containing human primary hepatocytes for hepatic metabolism, lymphoma cells as a model target for CHOP, and cardiomyocytes as a major site of off-target toxicity associated with this regimen. We found that a selective human CAR activator, CITCO (6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime), altered expression of key drug-metabolizing enzymes and transporters in human hepatocytes, which positively affects the metabolic profile of CHOP. Coadministration of CITCO and CHOP in the coculture model led to significantly enhanced cytotoxicity in lymphoma cells but not in cardiomyocytes. Moreover, the beneficial effects of CITCO were abrogated when CAR knockout HepaRG cells were used in the coculture model. Importantly, synergistic anticancer effects were observed between CITCO and CHOP, in that inclusion of CITCO alongside the CHOP regimen offers comparable antineoplastic activity toward lymphoma cells at significantly reduced drug concentrations, and the decreased CHOP load attenuates cardiotoxicity. Overall, these findings provide a potentially promising novel strategy for facilitating CHOP-based chemotherapy. Mol Cancer Ther; 15(3); 392–401. ©2016 AACR.
Phase I Study of DMOT4039A, an Antibody–Drug Conjugate Targeting Mesothelin, in Patients with Unresectable Pancreatic or Platinum-Resistant Ovarian Cancer
Authors: Weekes Colin D. , Lamberts Laetitia E. , Borad Mitesh J. , Voortman Johannes , McWilliams Robert R. , Diamond Jennifer R. , de Vries Elisabeth G.E. , Verheul Henk M. , Lieu Christopher H. , Kim George P. , Wang Yulei , Scales Suzie J. , Samineni Divya , Brunstein Flavia , Choi YounJeong , Maslyar Daniel J. , Colon-Otero Gerardo
Published: January 2016

DMOT4039A, a humanized anti-mesothelin mAb conjugated to the antimitotic agent monomethyl auristatin E (MMAE), was given to patients with pancreatic and ovarian cancer every 3 weeks (0.2–2.8 mg/kg; q3w) or weekly (0.8–1.2 mg/kg). A 3+3 design was used for dose escalation followed by expansion at the recommended phase II dose (RP2D) to evaluate safety and pharmacokinetics. Antitumor response was evaluated per RECIST 1.1 and serum CA19-9 or CA125 declines. Tumor mesothelin expression was determined by IHC. Seventy-one patients (40 pancreatic cancer; 31 ovarian cancer) were treated with DMOT4039A. For the q3w schedule (n = 54), the MTD and RP2D was 2.4 mg/kg, with dose-limiting toxicities of grade 3 hyperglycemia and grade 3 hypophosphatemia at 2.8 mg/kg. For the weekly schedule (n = 17), the maximum assessed dose was 1.2 mg/kg, with further dose escalations deferred because of toxicities limiting scheduled retreatment in later cycles, and therefore the RP2D level for the weekly regimen was determined to be 1 mg/kg. Across both schedules, the most common toxicities were gastrointestinal and constitutional. Treatment-related serious adverse events occurred in 6 patients; 4 patients continued treatment following dose reductions. Drug exposure as measured by antibody-conjugated MMAE and total antibody was generally dose proportional over all dose levels on both schedules. A total of 6 patients had confirmed partial responses (4 ovarian; 2 pancreatic) with DMOT4039A at 2.4 to 2.8 mg/kg i.v. q3w. DMOT4039A administered at doses up to 2.4 mg/kg q3w and 1.0 mg/kg weekly has a tolerable safety profile and antitumor activity in both pancreatic and ovarian cancer. Mol Cancer Ther; 15(3); 439–47. ©2016 AACR.
Posaconazole, a Second-Generation Triazole Antifungal Drug, Inhibits the Hedgehog Signaling Pathway and Progression of Basal Cell Carcinoma
Authors: Chen Baozhi , Trang Vinh , Lee Alex , Williams Noelle S. , Wilson Alexandra N. , Epstein Ervin H. , Tang Jean Y. , Kim James
Published: January 2016

Deregulation of Hedgehog (Hh) pathway signaling has been associated with the pathogenesis of various malignancies, including basal cell carcinomas (BCC). Inhibitors of the Hh pathway currently available or under clinical investigation all bind and antagonize Smoothened (SMO), inducing a marked but transient clinical response. Tumor regrowth and therapy failure were attributed to mutations in the binding site of these small-molecule SMO antagonists. The antifungal itraconazole was demonstrated to be a potent SMO antagonist with a distinct mechanism of action from that of current SMO inhibitors. However, itraconazole represents a suboptimal therapeutic option due to its numerous drug–drug interactions. Here, we show that posaconazole, a second-generation triazole antifungal with minimal drug–drug interactions and a favorable side-effect profile, is also a potent inhibitor of the Hh pathway that functions at the level of SMO. We demonstrate that posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but, similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent BCC in vivo. Our results suggest that posaconazole, alone or in combination with other Hh pathway antagonists, may be readily tested in clinical studies for the treatment of Hh-dependent cancers. Mol Cancer Ther; 15(5); 866–76. ©2016 AACR.
Cytomegalovirus Infection Minimally Affects the Frequencies of B-Cell Phenotypes in Peripheral Blood of Younger and Older Adults
Authors: Goldeck David , Oettinger Lilly , Janssen Nicole , Demuth Ilja , Steinhagen-Thiessen Elisabeth , Pawelec Graham
Published: January 2016

Background: An accumulation of late-differentiated CD8+ T-cells together with fewer B-cells and seropositivity for cytomegalovirus (CMV) characterises an ‘immune risk profile' associated with mortality in elderly people and represents one of the hallmarks of ‘immunosenescence'. Objectives: While differences in memory T-cell phenotypes between young and old people have been intensively studied, and the role of CMV is well-accepted as a driving force in this regard, the impact of CMV on B-cells, if any, has been relatively neglected thus far. Methods: Here, we avail ourselves of blood samples from participants of the Berlin Aging Study II (BASE-II) to compare peripheral blood B-cell differentiation phenotypes of 140 age- and gender-matched CMV-seronegative or -seropositive adults aged between 24 and 85 years using multicolour flow cytometry analysis. Results: We found that the frequencies of naïve B-cells within the CD19+ population were not significantly different in younger and older CMV-seronegative people. This was also true in CMV-seropositive subjects. The frequencies of late-differentiated B-cells were also not different in CMV-negative elderly and young. However, in marked contrast to the T-cell compartment, this was also true for late differentiated B-cells. Within age groups, the most marked differences in the distribution of B-cell phenotypes were between CMV-seronegative and -seropositive subjects, for both genders. Conclusion: These results emphasize the importance of including CMV serostatus in the analysis of immune signatures. Because the proportion of the population infected with CMV increases with age, the effect of CMV rather than age could confound analyses seeking age-associated changes to human immunity.
Association between Metabolic Syndrome and Bone Mineral Density - Data from the Berlin Aging Study II (BASE-II)
Authors: Eckstein Nils , Buchmann Nikolaus , Demuth Ilja , Steinhagen-Thiessen Elisabeth , Nikolov Jivko , Spira Dominik , Eckardt Rahel , Norman Kristina
Published: January 2016

Background: Decreased bone mineral density (BMD) has been linked to metabolic disorders, such as type 2 diabetes. However, results regarding the metabolic syndrome (MetS), a cluster of at least 3 of 5 cardiovascular risk parameters with potentially contradictory effects on BMD are still inconclusive. Objective: We investigated the effect of MetS and its single parameters on BMD at 3 sites in community-dwelling older subjects. Methods: 1,402 subjects (51.1% female, 68 ± 4 years old) from the Berlin Aging Study II (BASE-II) were included. MetS was defined as suggested by IDF/NHLBI/AHA. Insulin resistance (IR) was assessed by the homeostasis model of IR. BMD (lumbar spine, femur neck, hip) and trunk fat were measured by dual-energy X-ray absorptiometry. Osteoporosis was defined by a T score of ≤-2.5. Results: MetS was present in 29.6% of women and 41.7% of men. In regression models, we observed a positive association of MetS with the BMD of the lumbar spine (p = 0.005) and hip (p = 0.028) in women even after adjustment for risk factors, but no effect of the single parameters apart from IR. In contrast, there was no association between MetS and BMD in men. However, higher trunk fat and higher waist circumference were associated with lower levels of BMD in men with or without MetS (p < 0.05). Conclusion: We obtained different results in men and women. In women, the positive though slight effect of MetS on BMD could not be explained by single MetS components apart from IR. In men, central obesity was negatively associated with BMD, suggesting that the metabolic effects driven by visceral fat have a negative impact.
Elevated Serum Concentration of Chitinase 3-Like 1 is an Independent Prognostic Biomarker for Poor Survival in Lung Cancer Patients
Authors: Wang Jiying , Sheng Zhaoying , Yang Wenyan , Cai Yong
Published: January 2016

Background/Aims: The chitinase 3-like 1 (CHI3L1) has an important role in cancer progression, and high CHI3L1 expression is associated with the development and progression of cancers. Previous studies had been controversial with respect to the association between CHI3L1 expression and lung cancer prognosis. Thus, we performed a meta-analysis to investigate the prognostic value of CHI3L1 expression in lung cancer. Methods: We searched Pubmed, Embase, and Wanfang databases to identify eligible studies. Overall survival and disease free survival were collected from included studies. Pooled hazard ratios (HRs) with 95% confidence interval (95%CI) were calculated to estimate the association. Seven studies comprising 911 lung cancer patients were included in this meta-analysis. Results: The results showed high CHI3L1 expression was independently associated with poorer overall survival in lung cancer patients (HR = 1.71, 95%CI 1.24-2.37, P = 0.001). Subgroup analysis by histological type showed that high CHI3L1 expression was independently associated with poorer overall survival in both non small-cell lung cancer patients (HR = 2.23,95%CI 1.43-3.47, P < 0.001) and small-cell lung cancer patients (HR = 1.45, 95%CI 1.06-2.00, P = 0.021). In addition, sensitivity analysis by omitting single study by turns did not change the pooled outcomes obviously. Conclusion: Our results suggest that elevated serum CHI3L1 concentration is an independent prognostic biomarker for poorer survival in lung cancer patients.
Pannexin-1 Deficient Mice Have an Increased Susceptibility for Atrial Fibrillation and Show a QT-Prolongation Phenotype
Authors: Petric Stella , Klein Sofia , Dannenberg Lisa , Lahres Tillman , Clasen Lukas , Schmidt Klaus G. , Ding Zhaoping , Donner Birgit C.
Published: January 2016

Background/Aims: Pannexin-1 (Panx1) is an ATP release channel that is ubiquitously expressed and coupled to several ligand-gated receptors. In isolated cardiac myocytes, Panx1 forms large conductance channels that can be activated by Ca2+ release from the sarcoplasmic reticulum. Here we characterized the electrophysiological function of these channels in the heart in vivo, taking recourse to mice with Panx1 ablation. Methods: Cardiac phenotyping of Panx1 knock-out mice (Panx1-/-) was performed by employing a molecular, cellular and functional approach, including echocardiography, surface and telemetric ECG recordings with QT analysis, physical stress testing and quantification of heart rate variability. In addition, an in vivo electrophysiological study entailed programmed electrical stimulation using an intracardiac octapolar catheter. Results: Panx1 deficiency results in a higher incidence of AV-block, delayed ventricular depolarisation, significant prolongation of QT- and rate corrected QT-interval and a higher incidence of atrial fibrillation after intraatrial burst stimulation. Conclusion: Panx1 seems to play an important role in murine cardiac electrophysiology and warrants further consideration in the context of hereditary forms of atrial fibrillation.
Associations between Neighborhood Characteristics, Well-Being and Health Vary over the Life Course
Authors: Eibich Peter , Krekel Christian , Demuth Ilja , Wagner Gert G.
Published: January 2016

Background: Neighborhood characteristics are important determinants of individual health and well-being. For example, characteristics such as noise and pollution affect health directly, while other characteristics affect health and well-being by either providing resources (e.g. social capital in the neighborhood), which individuals can use to cope with health problems, or limiting the use thereof (e.g. crime). This also suggests that there might be age differentials in the impact of these characteristics, since individuals at different stages of life might need different resources. However, there is a lack of empirical evidence on age differentials in associations between well-being, health, and neighborhood characteristics. Objective: This paper studies associations between a wide range of neighborhood characteristics with the health and well-being of residents of the greater Berlin area. In particular, we focus on differences in the effects between younger (aged 20-35) and older (aged 60+) residents. Methods: We used data from the Berlin Aging Study II (312 younger and 993 older residents of the Berlin metropolitan area in Germany). We used survey data on health and well-being, combined these with subjective perceptions of the neighborhood, and geo-referenced indicators on the neighborhood, e.g. amenities (public transport, physicians, and hospitals). Results: The results show that access to public transportation is associated with better outcomes on all measures of health and well-being, and social support is associated with higher life satisfaction and better mental health. There are considerable differences between both age groups: while the associations between access to public transport and health and well-being are similar for both age groups, neighborhood social capital shows stronger associations for older residents. However, the difference is not always statistically significant. Conclusion: Having access to services is associated with better health and well-being regardless of age. Local policy makers should focus on lowering barriers to mobility in order to improve the health and well-being of the population. Since the social capital of a neighborhood is associated with better health and well-being among older residents, investments that increase social capital (e.g. community centers) might be warranted in neighborhoods with higher shares of older residents.
Genetic Burden Analyses of Phenotypes Relevant to Aging in the Berlin Aging Study II (BASE-II)
Authors: Lill Christina M. , Liu Tian , Norman Kristina , Meyer Antje , Steinhagen-Thiessen Elisabeth , Demuth Ilja , Bertram Lars
Published: January 2016

Background: Body mass index (BMI), bone mineral density (BMD), and telomere length are phenotypes that modulate the course of aging. Over 40% of their phenotypic variance is determined by genetics. Genome-wide association studies (GWAS) have recently uncovered >100 independent single-nucleotide polymorphisms (SNPs) showing genome-wide significant (p < 5 × 10-8) association with these traits. Objective: To test the individual and combined impact of previously reported GWAS SNPs on BMI, BMD, and relative leukocyte telomere length (rLTL) in ∼1,750 participants of the Berlin Aging Study II (BASE-II), a cohort consisting predominantly of individuals >60 years of age. Methods: Linear regression analyses were performed on a total of 101 SNPs and BMI, BMD measurements of the femoral neck (FN) and lumbar spine (LS), and rLTL. The combined effect of all trait-specific SNPs was evaluated by generating a weighted genomic profile score (wGPS) used in the association analyses. The predictive capability of the wGPS was estimated by determining the area under the receiver operating curve (AUC) for osteoporosis status (determined by BMD) with and without the wGPS. Results: Five loci showed experiment-wide significant association with BMI (FTO rs1558902, p = 1.80 × 10-5) or BMD (MEPE rs6532023, pFN = 5.40 × 10-4, pLS = 1.09 × 10-4; TNFRSF11B rs2062377, pLS = 8.70 × 10-4; AKAP11 rs9533090, pLS = 1.05 × 10-3; SMG6 rs4790881, pFN = 3.41 × 10-4) after correction for multiple testing. Several additional loci showed nominally significant (p < 0.05) association with BMI and BMD. The trait-specific wGPS was highly significantly associated with BMD (p < 2 × 10-16) and BMI (p = 1.10 × 10-6). No significant association was detected for rLTL in either single-SNP or wGPS-based analyses. The AUC for osteoporosis improved modestly from 0.762 (95% CI 0.733-0.800) to 0.786 (95% CI 0.756-0.823) and 0.785 (95% CI 0.757-0.824) upon inclusion of the FN- and LS-BMD wGPS, respectively. Conclusion: Our study provides an independent validation of previously reported genetic association signals for BMI and BMD in the BASE-II cohort. Additional studies are needed to pinpoint the factors underlying the proportion of phenotypic variance that remains unexplained by the current models.
Editorial
Authors: Gerstorf Denis , Bertram Lars , Lindenberger Ulman , Pawelec Graham , Demuth Ilja , Steinhagen-Thiessen Elisabeth , Wagner Gert G.
Published: January 2016

Human aging is characterized by large differences between and within older adults. Numerous factors are known to contribute to these differences, including genetic and immunological, somatic and medical, cognitive and behavioral, psychosocial and experiential, as well as socioeconomic and geospatial conditions. Continuing and expanding the scientific objectives of the Berlin Aging Study, the Berlin Aging Study II (BASE-II) seeks to comprehensively describe phenomena associated with aging and old age and to better understand the multiple different underlying factors and their interactions. To this end, BASE-II was established as a multi-institutional project combining and integrating interdisciplinary perspectives ranging from molecular genetics and immunology, geriatric medicine and psychology, to sociology and economics. In this Special Issue, we have compiled seven empirical analyses that feature examples of interdisciplinary insights that BASE-II provides by linking data across multiple levels of analyses at which human functioning and development occur in old age. Here, we provide an overview of the study, note commonalities between BASE-II and earlier studies, and highlight some of its unique qualities.
Incidence of Metachronous Distant Metastasis and ypN Classification Influence Patient Survival in Endosonographically Confirmed uT3 Rectal Cancer after Neoadjuvant Therapy and R0 Resection: A Historical Cohort Analysis
Authors: Troja Achim , Hempen Hans-Günther , Demmer Mareike , Antolovic Dalibor , Raab Hans-Rudolf
Published: January 2016

Background: Tumor response after neoadjuvant radiochemotherapy (NRC) prior to surgery and other parameters are likely to have an influence on the survival rate of patients suffering from T3 rectal cancer. Methods: 51 patients (17 female, 34 male; 59.0 years; Apache < 9 points: 95.1%; ASA I-II 88.3% and ASA III 11.8%) were treated with NRC (50.4 Gy; 5-fluorouracil/folinic acid) 4-6 weeks prior to surgery because of uT3 rectal cancer (G2: 96%; adenocarcinoma 86.3%; cUICC II 62.7%). NRC led to a tumor response (TR) (ypT0-ypT2) in 45.1% (ypT0N0M0 7.8%). Results: Neither the age of patients nor Apache/ASA score, histology, UICC staging, ypTNM, Dukes staging, infiltration of vessels, surgical procedure, local recurrence nor TR had a significant influence on the patients' survival time. Patients with metachronous distant metastasis (MDM) during the follow-up period (mean: 8.2 years; 1 month to 14.5 years) and patients with ypN1-ypN2 had a significantly shorter survival time. Conclusions: NRC prior to surgery leads to a remarkable TR rate but has no significant impact of TR on the patients' survival time. Occurrence of MDM during the follow-up period and ypN1/N2 status do have a greater influence. It is necessary to investigate larger cohorts of patients in the future to obtain more conclusive results and to define factors with influence on survival.
Recurrent Moderate Hypoglycemia Suppresses Brain-Derived Neurotrophic Factor Expression in the Prefrontal Cortex and Impairs Sensorimotor Gating in the Posthypoglycemic Period in Young Rats
Authors: Rao Raghavendra , Ennis Kathleen , Mitchell Eugena P. , Tran Phu V. , Gewirtz Jonathan C.
Published: January 2016

Recurrent hypoglycemia is common in infants and children. In developing rat models, recurrent moderate hypoglycemia leads to neuronal injury in the medial prefrontal cortex. To understand the effects beyond neuronal injury, 3-week-old male rats were subjected to 5 episodes of moderate hypoglycemia (blood glucose concentration, approx. 30 mg/dl for 90 min) once daily from postnatal day 24 to 28. Neuronal injury was determined using Fluoro-Jade B histochemistry on postnatal day 29. The effects on brain-derived neurotrophic factor (BDNF) and its cognate receptor, tyrosine kinase receptor B (TrkB) expression, which is critical for prefrontal cortex development, were determined on postnatal day 29 and at adulthood. The effects on prefrontal cortex-mediated function were determined by assessing the prepulse inhibition of the acoustic startle reflex on postnatal day 29 and 2 weeks later, and by testing for fear-potentiated startle at adulthood. Recurrent hypoglycemia led to neuronal injury confined primarily to the medial prefrontal cortex. BDNF/TrkB expression in the prefrontal cortex was suppressed on postnatal day 29 and was accompanied by lower prepulse inhibition, suggesting impaired sensorimotor gating. Following the cessation of recurrent hypoglycemia, the prepulse inhibition had recovered at 2 weeks. BDNF/TrkB expression in the prefrontal cortex had normalized and fear-potentiated startle was intact at adulthood. Recurrent moderate hypoglycemia during development has significant adverse effects on the prefrontal cortex in the posthypoglycemic period.