bluuebunny/crossref_metadata_2025 huggingface dataset:
Multiple Ischemic Infarctions, Pulmonary Edema, and Acute Renal Failure During an Episode of Diabetic Ketoacidosis in an Adult
Authors: Mishra Rahul K. , Nugent Kenneth M. , Dar Nabeel , Lado-Abeal Joaquin
Published: April 2012

The morbidity and mortality associated with diabetic ketoacidosis (DKA) often reflects the precipitating events, such as myocardial infarction. However, DKA can trigger a systemic inflammatory response with the potential for multiple complications. This 30-year-old woman with type 1 diabetes mellitus improved within 48 hours of admission with a standard DKA treatment protocol. However, subsequent chest X-rays revealed bilateral infiltrates consistent with pulmonary edema; she then developed fever, hypotension, and acute-on-chronic renal failure. An altered level of consciousness prompted evaluation with neuroimaging, which revealed ischemic infarcts in the right frontal, parieto-occipital, and temporal cortices and cerebellum correlating with a left-sided hemiparesis. This case illustrates the potential complexity in the pathogenesis and management of patients with DKA. This patient likely had a systemic inflammatory response syndrome with multiorgan failure during this episode of DKA. Patients with DKA need risk stratification for comorbid diseases on presentation and attention to vital signs, especially unexplained fever, evolving neurologic symptoms, and respiratory symptoms during the hospital course. This information can help dictate the time course for treatment; standard treatment protocols for patients with DKA may create a false sense of security in complex patients.
Pain Management for the Obese Sleep Apnea Patient
Authors: Schumacher Mark A.
Published: April 2012

Currently, one third of the US adult population is considered obese. As such, obese patients are a rapidly growing population of patients being admitted to ICU. The problems in managing pain for these patients, primarily perioperative and hospital-associated respiratory depression, are becoming increasingly apparent. New approaches for pain management are intended to minimize the life-threatening side effects of traditional pain control drugs (opioids) and to increase the therapeutic options with nonopioid agents. This article ( a) reviews the pathophysiology of obstructive sleep apnea and other related sleep apnea syndromes, ( b) describes risk factors for perioperative and hospital-associated respiratory depression, ( c) reviews other significant side effects of opioid analgesic agents, and finally ( d) summarizes the emerging consensus for the use of multimodal analgesia for managing pain in obese patients with obstructive sleep apnea.
Prolonged Length of Stay After Liver Transplantation
Authors: Young Andrew T. , Wagener Gebhard
Published: April 2012

Prolonged hospital length of stay after liver transplantation uses a large amount of hospital resources. The authors evaluated factors associated with prolonged hospital stay in a large single center series. Prolonged hospital stay was defined as more than 30 days. A total of 578 adult cadaveric liver transplants were included, and of these, 160 (27.7%) had a prolonged hospital stay. These patients had shorter waitlist time, higher preoperative MELD (model for end-stage liver disease) scores and received organs from donors with lower donor risk indices. In multivariate analysis, only preoperative MELD score remained significant. Postoperatively, there was no difference in the incidence of acute kidney injury; however, patients with prolonged hospital stay were more likely to have early allograft dysfunction and a higher 90-day mortality.
Spry1 as a novel regulator of erythropoiesis, EPO/EPOR target, and suppressor of JAK2
Authors: Sathyanarayana Pradeep , Dev Arvind , Pradeep Anamika , Ufkin Melanie , Licht Jonathan D. , Wojchowski Don M.
Published: April 2012

Sprouty proteins are established modifiers of receptor tyrosine kinase (RTK) signaling and play important roles in vasculogenesis, bone morphogenesis, and renal uteric branching. Little is understood, however, concerning possible roles for these molecular adaptors during hematopoiesis. Within erythroid lineage, Spry1 was observed to be selectively and highly expressed at CFU-e to erythroblast stages. In analyses of possible functional roles, an Mx1-Cre approach was applied to conditionally delete Spry1. At steady state, Spry1 deletion selectively perturbed erythroid development and led to reticulocytosis plus heightened splenic erythropoiesis. When challenged by hemolysis, Spry1-null mice exhibited worsened anemia and delayed recovery. During short-term marrow transplantation, Spry1-null donor marrow also failed to efficiently rescue the erythron. In each anemia model, however, hyperexpansion of erythroid progenitors was observed. Spry function depends on phosphorylation of a conserved N-terminal PY motif. Through an LC-MS/MS approach, Spry1 was discovered to be regulated via the erythropoietin receptor (EPOR), with marked EPO-induced Spry1-PY53 phosphorylation observed. When EPOR signaling pathways were analyzed within Spry1-deficient erythroid progenitors, hyperactivation of not only Erk1,2 but also Jak2 was observed. Studies implicate Spry1 as a novel regulator of erythropoiesis during anemia, transducer of EPOR signals, and candidate suppressor of Jak2 activity.
Association between polymorphism in the FTO gene and growth and carcass traits in pig crosses
Authors: Dvořáková Věra , Bartenschlager Heinz , Stratil Antonín , Horák Pavel , Stupka Roman , Čítek Jaroslav , Šprysl Michal , Hrdlicová Anna , Geldermann Hermann
Published: April 2012

Background

Independent studies have shown that several single nucleotide polymorphisms (SNP) in the human FTO (fat mass and obesity associated) gene are associated with obesity. SNP have also been identified in the pig FTO gene, among which some are associated with selected fat-deposition traits in F2 crosses and commercial populations. In this study, using both commercial pig populations and an experimental Meishan × Pietrain F2 population, we have investigated the association between one FTO SNP and several growth and carcass traits. Association analyses were performed with the FTO polymorphism either alone or in combination with polymorphisms in flanking loci.

Methods

SNP (FM244720:g.400C>G) in exon 3 of porcine FTO was genotyped by PCR-RFLP and tested for associations with some growth, carcass and fat-related traits. Proportions of genetic variance of four pig chromosome 6 genes (FTO, RYR1, LIPE and TGFB1) on selected traits were evaluated using single- and multi-locus models.

Results

Linkage analysis placed FTO on the p arm of pig chromosome 6, approximately 22 cM from RYR1. In the commercial populations, allele C of the FTO SNP was significantly associated with back fat depth and allele G with muscling traits. In the Meishan × Pietrain F2 pigs, heterozygotes with allele C from the Pietrain sows and allele G from the Meishan boar were more significantly associated with fat-related traits compared to homozygotes with allele G from the Pietrain and allele G from the Meishan breed. In single- and multi-locus models, genes RYR1, TGFB1 and FTO showed high associations. The contribution in genetic variance from the polymorphism in the FTO gene was highest for back fat depth, meat area on the musculus longissimus lumborum et thoracis tissues and metabolite glucose-6-phosphate dehydrogenase.

Conclusions

Our results show that in pig, FTO influences back fat depth in the commercial populations, while in the Meishan × Pietrain F2 pigs with a CG genotype, heterosis occurs for several fat-related traits.
A comparative study of nemertean complete mitochondrial genomes, including two new ones for Nectonemertes cf. mirabilis and Zygeupolia rubens, may elucidate the fundamental pattern for the phylum Nemertea
Authors: Chen Hai-Xia , Sun Shi-Chun , Sundberg Per , Ren Wei-Cheng , Norenburg Jon L
Published: April 2012

Background

The mitochondrial genome is important for studying genome evolution as well as reconstructing the phylogeny of organisms. Complete mitochondrial genome sequences have been reported for more than 2200 metazoans, mainly vertebrates and arthropods. To date, from a total of about 1275 described nemertean species, only three complete and two partial mitochondrial DNA sequences from nemerteans have been published. Here, we report the entire mitochondrial genomes for two more nemertean species: Nectonemertes cf. mirabilis and Zygeupolia rubens.

Results

The sizes of the entire mitochondrial genomes are 15365 bp for N. cf. mirabilis and 15513 bp for Z. rubens. Each circular genome contains 37 genes and an AT-rich non-coding region, and overall nucleotide composition is AT-rich. In both species, there is significant strand asymmetry in the distribution of nucleotides, with the coding strand being richer in T than A and in G than C. The AT-rich non-coding regions of the two genomes have some repeat sequences and stem-loop structures, both of which may be associated with the initiation of replication or transcription. The 22 tRNAs show variable substitution patterns in nemerteans, with higher sequence conservation in genes located on the H strand. Gene arrangement of N. cf. mirabilis is identical to that of Paranemertes cf. peregrina, both of which are Hoplonemertea, while that of Z. rubens is the same as in Lineus viridis, both of which are Heteronemertea. Comparison of the gene arrangements and phylogenomic analysis based on concatenated nucleotide sequences of the 12 mitochondrial protein-coding genes revealed that species with closer relationships share more identical gene blocks.

Conclusion

The two new mitochondrial genomes share many features, including gene contents, with other known nemertean mitochondrial genomes. The tRNA families display a composite substitution pathway. Gene order comparison to the proposed ground pattern of Bilateria and some lophotrochozoans suggests that the nemertean ancestral mitochondrial gene order most closely resembles the heteronemertean type. Phylogenetic analysis proposes a sister-group relationship between Hetero- and Hoplonemertea, which supports one of two recent alternative hypotheses of nemertean phylogeny.
Loss of genetic diversity as a signature of apricot domestication and diffusion into the Mediterranean Basin
Authors: Bourguiba Hedia , Audergon Jean-Marc , Krichen Lamia , Trifi-Farah Neila , Mamouni Ali , Trabelsi Samia , D’Onofrio Claudio , Asma Bayram M , Santoni Sylvain , Khadari Bouchaib
Published: April 2012

Background

Domestication generally implies a loss of diversity in crop species relative to their wild ancestors because of genetic drift through bottleneck effects. Compared to native Mediterranean fruit species like olive and grape, the loss of genetic diversity is expected to be more substantial for fruit species introduced into Mediterranean areas such as apricot (Prunus armeniacaL.), which was probably primarily domesticated in China. By comparing genetic diversity among regional apricot gene pools in several Mediterranean areas, we investigated the loss of genetic diversity associated with apricot selection and diffusion into the Mediterranean Basin.

Results

According to the geographic origin of apricots and using Bayesian clustering of genotypes, Mediterranean apricot (207 genotypes) was structured into three main gene pools: ‘Irano-Caucasian’, ‘North Mediterranean Basin’ and ‘South Mediterranean Basin’. Among the 25 microsatellite markers used, only one displayed deviations from the frequencies expected under neutrality. Similar genetic diversity parameters were obtained within each of the three main clusters using both all SSR loci and only 24 SSR loci based on the assumption of neutrality. A significant loss of genetic diversity, as assessed by the allelic richness and private allelic richness, was revealed from the ‘Irano-Caucasian’ gene pool, considered as a secondary centre of diversification, to the northern and southwestern Mediterranean Basin. A substantial proportion of shared alleles was specifically detected when comparing gene pools from the ‘North Mediterranean Basin’ and ‘South Mediterranean Basin’ to the secondary centre of diversification.

Conclusions

A marked domestication bottleneck was detected with microsatellite markers in the Mediterranean apricot material, depicting a global image of two diffusion routes from the ‘Irano-Caucasian’ gene pool: North Mediterranean and Southwest Mediterranean. This study generated genetic insight that will be useful for management of Mediterranean apricot germplasm as well as genetic selection programs related to adaptive traits.
Expression and purification of the p75 neurotrophin receptor transmembrane domain using a ketosteroid isomerase tag
Authors: Li Qingxin , Chen Angela Shuyi , Gayen Shovanlal , Kang CongBao
Published: April 2012

Background

Receptors with a single transmembrane (TM) domain are essential for the signal transduction across the cell membrane. NMR spectroscopy is a powerful tool to study structure of the single TM domain. The expression and purification of a TM domain inEscherichia coli(E.coli) is challenging due to its small molecular weight. Although ketosteroid isomerase (KSI) is a commonly used affinity tag for expression and purification of short peptides, KSI tag needs to be removed with the toxic reagent cyanogen bromide (CNBr).

Result

The purification of the TM domain of p75 neurotrophin receptor using a KSI tag with the introduction of a thrombin cleavage site is described herein. The recombinant fusion protein was refolded into micelles and was cleaved with thrombin. Studies showed that purified protein could be used for structural study using NMR spectroscopy.

Conclusions

These results provide another strategy for obtaining a single TM domain for structural studies without using toxic chemical digestion or acid to remove the fusion tag. The purified TM domain of p75 neurotrophin receptor will be useful for structural studies.
Patient-oriented simulation based on Monte Carlo algorithm by using MRI data
Authors: Chuang Ching-Cheng , Lee Yu-Tzu , Chen Chung-Ming , Hsieh Yao-Sheng , Liu Tsan-Chi , Sun Chia-Wei
Published: April 2012

Background

Although Monte Carlo simulations of light propagation in full segmented three-dimensional MRI based anatomical models of the human head have been reported in many articles. To our knowledge, there is no patient-oriented simulation for individualized calibration with NIRS measurement. Thus, we offer an approach for brain modeling based on image segmentation process within vivoMRI T1 three-dimensional image to investigate the individualized calibration for NIRS measurement with Monte Carlo simulation.

Methods

In this study, an individualized brain is modeled based onin vivoMRI 3D image as five layers structure. The behavior of photon migration was studied for this individualized brain detections based on three-dimensional time-resolved Monte Carlo algorithm. During the Monte Carlo iteration, all photon paths were traced with various source-detector separations for characterization of brain structure to provide helpful information for individualized design of NIRS system.

Results

Our results indicate that the patient-oriented simulation can provide significant characteristics on the optimal choice of source-detector separation within 3.3 cm of individualized design in this case. Significant distortions were observed around the cerebral cortex folding. The spatial sensitivity profile penetrated deeper to the brain in the case of expanded CSF. This finding suggests that the optical method may provide not only functional signal from brain activation but also structural information of brain atrophy with the expanded CSF layer. The proposed modeling method also provides multi-wavelength for NIRS simulation to approach the practical NIRS measurement.

Conclusions

In this study, the three-dimensional time-resolved brain modeling method approaches the realistic human brain that provides useful information for NIRS systematic design and calibration for individualized case with prior MRI data.
Tubulobulbar complex: Cytoskeletal remodeling to release spermatozoa
Authors: Upadhyay Rahul D , Kumar Anita V , Ganeshan Malti , Balasinor Nafisa H
Published: April 2012

Tubulobulbar complexes (TBCs) are actin-based structures that help establish close contact between Sertoli–Sertoli cells or Sertoli–mature germ cells (spermatids) in the seminiferous tubules of the testes. They are actin-rich push-through devices that eliminate excess spermatid cytoplasm and prepare mature spermatids for release into the tubular lumen. Just prior to spermiation, the elongated spermatid interacts with the Sertoli cell via an extensive structure comprising various adhesion molecules called the apical ectoplasmic specialization which is partially replaced by the apical TBC, on the concave surface of the spermatid head. The sperm release process involves extensive restructuring, namely the disassembly and reassembly of junctions at the Sertoli–spermatid interface in the seminiferous epithelium. Based on the presence of different classes of molecules in the TBCs or the defects observed in the absence of TBCs, the main functions attributed to TBCs are elimination of excess spermatid cytoplasm, endocytosis and recycling of junctional molecules, shaping of the spermatid acrosome, and forming transient anchoring devices for mature spermatids before they are released. This review summarizes the recent findings that focus on the role of TBCs in cell cytoskeleton restructuring during sperm release in the testes and the molecular mechanism involved.
Fixed point results for multivalued contractive maps
Authors: Bin Dehaish B A , Latif Abdul
Published: April 2012

Using the concept of u-distance, we prove a fixed point theorem for multivalued contractive maps. We also establish a multivalued version of the Caristi's fixed point theorem and common fixed point result. Consequently, several known fixed point results are either improved or generalized including the corresponding fixed point results of Caristi, Mizoguchi-Takahashi, Kada et al., Suzuki-Takahashi, Suzuki, and Ume.

Mathematics Subject Classification (2000): 47H10; 54H25.
Inhibition of Ca2+/Calmodulin-Dependent Protein Kinase II Reverses Oxaliplatin-Induced Mechanical Allodynia in Rats
Authors: Shirahama Masafumi , Ushio Soichiro , Egashira Nobuaki , Yamamoto Shota , Sada Hikaru , Masuguchi Ken , Kawashiri Takehiro , Oishi Ryozo
Published: April 2012

Background:

Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes severe peripheral neuropathy. We previously reported that oxaliplatin (4 mg/kg, i.p., twice a week) induces mechanical allodynia in the late phase in rats, and that spinal NR2B-containig N-methyl-D-aspartate (NMDA) receptors are involved in the oxaliplatin-induced mechanical allodynia. In the present study, we investigated the involvement of Ca2+/calmodulin dependent protein kinase II (CaMKII), which is a major intracellular protein kinase and is activated by NMDA receptor-mediated Ca2+ influx, in the oxaliplatin-induced mechanical allodynia in rats.

Results:

An increase of CaMKII phosphorylation was found in the spinal cord (L4-6) of oxaliplatin-treated rats. This increased CaMKII phosphorylation was reversed by intrathecal injection of a selective CaMKII inhibitor KN-93 (50 nmol, i.t.) and a selective NR2B antagonist Ro 25–6981 (300 nmol, i.t.). Moreover, acute administration of KN-93 (50 nmol, i.t.) strongly reversed the oxaliplatin-induced mechanical allodynia in von Frey test, while it did not affect the oxaliplatin-induced cold hyperalgesia in acetone test. Similarly, oral administration of trifluoperazine (0.1 and 0.3 mg/kg, p.o.), which is an antipsychotic drug and inhibits calmodulin, reduced both mechanical allodynia and increased CaMKII phosphorylation. On the other hand, trifluoperazine at the effective dose (0.3 mg/kg) had no effect on the paw withdrawal threshold in intact rats. In addition, trifluoperazine at the same dose did not affect the motor coordination in rota-rod test in intact and oxaliplatin-treated rats.

Conclusions:

These results suggest that CaMKII is involved in the oxaliplatin-induced mechanical allodynia, and trifluoperazine may be useful for the treatment of oxaliplatin-induced peripheral neuropathy in clinical setting.
Clinicopathological significance of SOX4 expression in primary gallbladder carcinoma
Authors: Wang Chengguo , Zhao Huadong , Lu Jianguo , Yin Jikai , Zang Li , Song Nuan , Dong Rui , Wu Tao , Du Xilin
Published: April 2012

Aim

SOX4, as a member of the SRY-related HMG-box (SOX) transcription factor family, has been demonstrated to be involved in tumorigenesis of many human malignancies; however, its role in primary gallbladder carcinoma (PGC) is still largely unknown. The aim of this study was to investigate SOX4 expression in PGC and its prognostic significance.

Methods

From 1997 to 2006, 136 patients underwent resection for PGC. The median follow-up was 12.8 months. Immunostainings for SOX4 were performed on these archival tissues. The correlation of SOX4 expression with clinicopathological features including survival was analyzed.

Results

SOX4 was expressed in 75.0% (102/136) of PGC but not in the normal epithelium of the gallbladder. In addition, the over-expression of SOX4 was significantly associated with low histologic grade (P = 0.02), low pathologic T stage (P = 0.02), and early clinical stage (P = 0.03). The levels of SOX4 immunostainings in PGC tissues with positive nodal metastasis were also significantly lower than those without (P = 0.01). Moreover, Kaplan-Meier curves showed that SOX4 over-expression was significantly related to better overall (P = 0.008) and disease-free survival (P = 0.01). Furthermore, multivariate analyses showed that SOX4 expression was an independent risk factor for both overall (P = 0.03, hazard ratio, 3.682) and disease-free survival (P = 0.04, hazard ratio, 2.215).

Conclusion

Our data indicate for the first time that the over-expression of SOX4 in PGC was significantly correlated with favorable clinicopathologic features and was an independent prognostic factor for better overall and disease-free survival in patients. Therefore, SOX4 might be an auxiliary parameter for predicting malignant behavior for PGC.

Virtual slides

The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1534825818694957.
The influence of oestrous substances on cyclicity and oestrous behaviour in dairy heifers
Authors: Nordéus Kristina , Båge Renée , Gustafsson Hans , Humblot Patrice , Söderquist Lennart
Published: April 2012

Background

Declining fertility is a major concern for dairy farmers today. One explanation is shorter and weaker expression of oestrus in dairy cows making it difficult to determine optimal time for artificial insemination (AI). Chemical communication is of interest in the search for tools to detect oestrus or to synchronise or enhance oestrous periods. Pheromones, used in chemical communication within species, can influence reproduction in different ways. The aim here was to investigate whether oestrous cycle length, and duration and intensity of oestrous expression in dairy heifers could be manipulated through exposure to pheromones in oestrual substances from other females.

Methods

Beginning on day 16 of two consecutive control oestrous cycles, ten heifers of the Swedish Red Breed (SRB) were exposed to water. During the two following cycles the heifers were exposed to urine and vaginal mucus, obtained from cows in oestrus. Cyclicity parameters were monitored through hormone measurements, oestrus detection and ultrasonographic examination.

Results

We found no difference in cycle length or in duration of standing oestrus between control and treatment. We did, however, find a tendency of interaction between type of exposure (control or treatment) and cycle number within type of exposure for cycle length (p = 0.068), with the length differing less between the treatment cycles. We also found a tendency of effect of type of exposure on maximal concentration (p = 0.073) and sum of concentrations (p = 0.063) of LH during the LH surge, with values being higher for the control cycles. There were also significant differences in when the different signs of oestrus occurred and in the intensity of oestrous expression. The score for oedema and hyperaemia of external genitalia was significantly higher (p = 0.004) for the control cycles and there was also a significant interaction between type of exposure and time period for restlessness (p = 0.011), with maximum score occurring earlier for treatment cycles.

Conclusions

No evidence of altered oestrous cycle length or duration of oestrus after exposure of females to oestrous substances from other females was found. Expression of oestrus, and maybe also LH secretion, however, seemed influenced by the exposure, with the effect of treatment being suppressive rather than enhancing.
An observational study of compliance with the Scandinavian guidelines for management of minimal, mild and moderate head injury
Authors: Heskestad Ben , Waterloo Knut , Ingebrigtsen Tor , Romner Bertil , Harr Marianne Efskind , Helseth Eirik
Published: April 2012

Background

The Scandinavian guidelines for management of minimal, mild and moderate head injuries were developed to provide safe and cost effective assessment of head injured patients. In a previous study conducted one year after publication and implementation of the guidelines (2003), we showed low compliance, involving over-triage with computed tomography (CT) and hospital admissions. The aim of the present study was to investigate guideline compliance after an educational intervention.

Methods

We evaluated guideline compliance in the management of head injured patients referred to the University Hospital of Stavanger, Norway. The findings from the previous study in 2003 were communicated to the hospitals physicians, and a feed-back loop training program for guideline implementation was conducted. All patients managed during the months January through June in the years 2005, 2007 and 2009 were then identified with an electronic search in the hospitals patient administrative database, and the patient files were reviewed. Patients were classified according to the Head Injury Severity Scale, and the management was classified as compliant or not with the guideline.

Results

The 1 180 patients were 759 (64%) males and 421 (36%) females with a mean age of 31.5 (range 0-97) years. Over all, 738 (63%) patients were managed in accordance with the guidelines and 442 (37%) were not. Compliance was not significantly different between minimal (56%) and mild (59%) injuries, while most moderate (93%) injuries were managed in accordance with the guidelines (p < 0.05). Noncompliance was caused by overtriage in 362 cases (30%) and undertriage in 80 (7%). Guideline compliance was 54% in 2005, 71% in 2007, and 64% in 2009.

Conclusions

This study shows higher guideline compliance after an educational intervention involving feed-back on performance. A substantial number of patients are exposed to over-triage, involving unnecessary radiation from CT examinations, and unnecessary costs from hospital admissions.
Kinematic and dynamic gait compensations resulting from knee instability in a rat model of osteoarthritis
Authors: Allen Kyle D , Mata Brian A , Gabr Mostafa A , Huebner Janet L , Adams Samuel B , Kraus Virginia B , Schmitt Daniel O , Setton Lori A
Published: April 2012

Introduction

Osteoarthritis (OA) results in pain and disability; however, preclinical OA models often focus on joint-level changes. Gait analysis is one method used to evaluate both preclinical OA models and OA patients. The objective of this study is to describe spatiotemporal and ground reaction force changes in a rat medial meniscus transection (MMT) model of knee OA and to compare these gait measures with assays of weight bearing and tactile allodynia.

Methods

Sixteen rats were used in the study. The medial collateral ligament (MCL) was transected in twelve Lewis rats (male, 200 to 250 g); in six rats, the medial meniscus was transected, and the remaining six rats served as sham controls. The remaining four rats served as naïve controls. Gait, weight-bearing as measured by an incapacitance meter, and tactile allodynia were assessed on postoperative days 9 to 24. On day 28, knee joints were collected for histology. Cytokine concentrations in the serum were assessed with a 10-plex cytokine panel.

Results

Weight bearing was not affected by sham or MMT surgery; however, the MMT group had decreased mechanical paw-withdrawal thresholds in the operated limb relative to the contralateral limb (P = 0.017). The gait of the MMT group became increasingly asymmetric from postoperative days 9 to 24 (P = 0.020); moreover, MMT animals tended to spend more time on their contralateral limb than their operated limb while walking (P < 0.1). Ground reaction forces confirmed temporal shifts in symmetry and stance time, as the MMT group had lower vertical and propulsive ground reaction forces in their operated limb relative to the contralateral limb, naïve, and sham controls (P < 0.05). Levels of interleukin 6 in the MMT group tended to be higher than naïve controls (P = 0.072). Histology confirmed increased cartilage damage in the MMT group, consistent with OA initiation. Post hoc analysis revealed that gait symmetry, stance time imbalance, peak propulsive force, and serum interleukin 6 concentrations had significant correlations to the severity of cartilage lesion formation.

Conclusion

These data indicate significant gait compensations were present in the MMT group relative to medial collateral ligament (MCL) injury (sham) alone and naïve controls. Moreover, these data suggest that gait compensations are likely driven by meniscal instability and/or cartilage damage, and not by MCL injury alone.
Predictors of Early Death Risk in Older Patients Treated With First-Line Chemotherapy for Cancer
Authors: Soubeyran Pierre , Fonck Marianne , Blanc-Bisson Christèle , Blanc Jean-Frédéric , Ceccaldi Joël , Mertens Cécile , Imbert Yves , Cany Laurent , Vogt Luc , Dauba Jerôme , Andriamampionona Francis , Houédé Nadine , Floquet Anne , Chomy Francois , Brouste Véronique , Ravaud Alain , Bellera Carine , Rainfray Muriel
Published: April 2012

Purpose

Objective factors for making choices about the treatment of elderly patients with cancer are lacking. This investigation aimed to help physicians select appropriate treatments through the identification of factors that predict early death (< 6 months) after initiation of chemotherapy treatment.

Patients and Methods

Previously untreated patients greater than 70 years of age who were scheduled for first-line chemotherapy for various types of cancer were included. Baseline abbreviated comprehensive geriatric assessment (aCGA), including the Mini-Mental State Exam, Timed Get Up and Go (GUG), Activities of Daily Living (ADL), Instrumental Activities in Daily Living (IADL), Mini Nutritional Assessment (MNA), Geriatric Depression Scale (GDS15), and comorbidities index (Cumulative Index Rating Scale-Geriatric), was carried out. Prognostic factors of early death were sought from aCGA results and traditional oncology measures.

Results

A total of 348 patients were included across 12 centers in Southwest France (median age, 77.45 years; ratio of men to women, 1.47; advanced disease, 65%). Abnormal aCGA scores were observed for 18.1% of patients on the ADL, 73.0% of patients on the IADL, 24.1% of patients on the GUG, 19.0% of patients on the MMS, 44.0% of patients on the GDS15, and 64.9% of patients on the MNA. Advanced disease (odds ratio [OR], 3.9; 95% CI, [1.58 to 9.73]), a low MNA score (OR 2.77; 95% CI, [1.24 to 6.18]), male sex (OR, 2.40; 95% CI, [1.2 to 4.82]), and long GUG (OR, 2.55; 95% CI, [1.32 to 4.94] were associated with higher risk of early death.

Conclusion

In patients greater than 70 years of age with cancer, advanced disease, a low MNA score, and poor mobility predicted early death. We recommend that the MNA and GUG, performed by a trained nurse, be maintained as part of routine pretreatment workup in these patients to identify at-risk patients and to inform the decision-making process for chemotherapy.
Accelerated Radiotherapy With Carbogen and Nicotinamide for Laryngeal Cancer: Results of a Phase III Randomized Trial
Authors: Janssens Geert O. , Rademakers Saskia E. , Terhaard Chris H. , Doornaert Patricia A. , Bijl Hendrik P. , van den Ende Piet , Chin Alim , Marres Henri A. , de Bree Remco , van der Kogel Albert J. , Hoogsteen Ilse J. , Bussink Johannes , Span Paul N. , Kaanders Johannes H.
Published: April 2012

Purpose

To report the results from a randomized trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen inhalation and nicotinamide (ARCON) in laryngeal cancer.

Patients and Methods

Patients with cT2-4 squamous cell laryngeal cancer were randomly assigned to AR (68 Gy within 36 to 38 days) or ARCON. To limit the risk of laryngeal necrosis, ARCON patients received 64 Gy on the laryngeal cartilage. The primary end point was local control. Secondary end points were regional control, larynx preservation, toxicity, disease-free survival, and overall survival. In a translational side study, the hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies.

Results

From April 2001 to February 2008, 345 patients were accrued. After a median follow-up of 44 months, local tumor control rate at 5 years was 78% for AR versus 79% for ARCON (P = .80), with larynx preservation rates of 84% and 87%, respectively (P = .48). The 5-year regional control was significantly better with ARCON (93%) compared with AR (86%, P = .04). The improvement in regional control was specifically observed in patients with hypoxic tumors and not in patients with well-oxygenated tumors (100% v 55%, respectively; P = .01). AR and ARCON produced equal levels of toxicity.

Conclusion

Despite lack of benefit in local tumor control for advanced laryngeal cancers, a significant gain in regional control rate, with equal levels of toxicity, was observed in favor of ARCON. The poor regional control of patients with hypoxic tumors is specifically countered by ARCON treatment.
Cladribine, But Not Fludarabine, Added to Daunorubicin and Cytarabine During Induction Prolongs Survival of Patients With Acute Myeloid Leukemia: A Multicenter, Randomized Phase III Study
Authors: Holowiecki Jerzy , Grosicki Sebastian , Giebel Sebastian , Robak Tadeusz , Kyrcz-Krzemien Slawomira , Kuliczkowski Kazimierz , Skotnicki Aleksander B. , Hellmann Andrzej , Sulek Kazimierz , Dmoszynska Anna , Kloczko Janusz , Jedrzejczak Wieslaw W. , Zdziarska Barbara , Warzocha Krzysztof , Zawilska Krystyna , Komarnicki Mieczysław , Kielbinski Marek , Piatkowska-Jakubas Beata , Wierzbowska Agnieszka , Wach Malgorzata , Haus Olga
Published: April 2012

Purpose

The goal of this study was to evaluate whether the addition of a purine analog, cladribine or fludarabine, to the standard induction regimen affects the outcome of adult patients with acute myeloid leukemia (AML).

Patients and Methods

A cohort of 652 untreated AML patients with median age 47 years (range, 17 to 60 years) were randomly assigned to receive one of three induction regimens: DA (daunorubicin plus cytarabine), DAC (DA plus cladribine), or DAF (DA plus fludarabine). Postremission treatment was the same for all arms.

Results

Complete remission rate in the DAC arm was higher compared with the DA arm (67.5% v 56%; P = .01) as a consequence of reduced incidence of resistant disease (21% v 34%; P = .004). There was no significant difference in early outcome between the DAF and DA arms. The probability of overall survival was improved for the DAC arm (45% ± 4% at 3 years) compared with the DA arm (33% ± 4%; P = .02), and leukemia-free survival was comparable. Long-term outcome did not differ significantly for the comparison of the DAF and DA arms. A survival advantage of the DAC arm over the DA arm was observed among patients age 50 years or older (P = .005), those with initial leukocyte count above 50 × 109/L (P = .03), and those with unfavorable karyotype (P = .03). DAF revealed a significant advantage over DA in patients with adverse karyotype (P = .02).

Conclusion

The addition of cladribine to the standard induction regimen is associated with increased rate of complete remission and improved survival of adult patients with AML.
Phase II Study of Ganitumab, a Fully Human Anti–Type-1 Insulin-Like Growth Factor Receptor Antibody, in Patients With Metastatic Ewing Family Tumors or Desmoplastic Small Round Cell Tumors
Authors: Tap William D. , Demetri George , Barnette Phillip , Desai Jayesh , Kavan Petr , Tozer Richard , Benedetto Pasquale W. , Friberg Gregory , Deng Hongjie , McCaffery Ian , Leitch Ian , Badola Sunita , Chang Sung , Zhu Min , Tolcher Anthony
Published: April 2012

Purpose

Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT).

Patients and Methods

Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated.

Results

Thirty-eight patients (22 with EFT; 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed.

Conclusion

Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT.
Randomized Phase II Trial of Erlotinib With and Without Entinostat in Patients With Advanced Non–Small-Cell Lung Cancer Who Progressed on Prior Chemotherapy
Authors: Witta Samir E. , Jotte Robert M. , Konduri Katrik , Neubauer Marcus A. , Spira Alexander I. , Ruxer Robert L. , Varella-Garcia Marileila , Bunn Paul A. , Hirsch Fred R.
Published: April 2012

Purpose

Histone deacetylase inhibitors (HDACis) have been shown to overcome resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) linked to epigenetic changes and epithelial-mesenchymal transition (EMT) state. This randomized phase II study evaluated the outcome of erlotinib with and without the isoform selective HDACi, entinostat.

Patients and Methods

Previously treated patients with stage IIIB/IV non–small-cell lung cancer, no prior EGFR-TKIs, and performance status ≤ 2 were randomly administered erlotinib 150 mg on days 1 through 28 plus entinostat 10 mg orally on days 1 and 15 every 28 days (EE) or erlotinib plus placebo (EP). The primary end point was 4-month progression-free survival (PFS) rate with additional end points including 6-month PFS rate, PFS, and overall survival (OS). Exploratory analyses included EMT- and EGFR-related biomarker analysis on archival tissue.

Results

One hundred thirty-two patients were enrolled (EE, 67; EP, 65). The 4-month PFS rate was comparable for both groups (EE, 18% v EP, 20%; P = .7). In the subset of patients with high E-cadherin levels, OS was longer in the EE group compared with the EP group (9.4 v 5.4 months; hazard ratio, 0.35; 95% CI, 0.13 to 0.92; P = .03) with a corresponding trend toward increased PFS. The adverse event (AE) profile was acceptable, with rash, fatigue, diarrhea, and nausea the most common AEs in both groups.

Conclusion

Erlotinib combined with entinostat did not improve the outcomes of patients in the overall study population when compared with erlotinib monotherapy. High E-cadherin expression levels at time of diagnosis indicate an increased sensitivity to HDACi/EGFR-TKI inhibition providing the basis for a biomarker-driven validation study.
Prospective, Observational Study of Pain and Analgesic Prescribing in Medical Oncology Outpatients With Breast, Colorectal, Lung, or Prostate Cancer
Authors: Fisch Michael J. , Lee Ju-Whei , Weiss Matthias , Wagner Lynne I. , Chang Victor T. , Cella David , Manola Judith B. , Minasian Lori M. , McCaskill-Stevens Worta , Mendoza Tito R. , Cleeland Charles S.
Published: April 2012

Purpose

Pain is prevalent among patients with cancer, yet pain management patterns in outpatient oncology are poorly understood.

Patients and Methods

A total of 3,123 ambulatory patients with invasive cancer of the breast, prostate, colon/rectum, or lung were enrolled onto this prospective study regardless of phase of care or stage of disease. At initial assessment and 4 to 5 weeks later, patients completed a 25-item measure of pain, functional interference, and other symptoms. Providers recorded analgesic prescribing. The pain management index was calculated to assess treatment adequacy.

Results

Of the 3,023 patients we identified to be at risk for pain, 2,026 (67%) reported having pain or requiring analgesics at initial assessment; of these 2,026 patients, 670 (33%) were receiving inadequate analgesic prescribing. We found no difference in treatment adequacy between the initial and follow-up visits. Multivariable analysis revealed that the odds of a non-Hispanic white patient having inadequate pain treatment were approximately half those of a minority patient after adjusting for other explanatory variables (odds ratio, 0.51; 95% CI, 0.37 to 0.70; P = .002). Other significant predictors of inadequate pain treatment were having a good performance status, being treated at a minority treatment site, and having nonadvanced disease without concurrent treatment.

Conclusion

Most outpatients with common solid tumors must confront issues related to pain and the use of analgesics. There is significant disparity in pain treatment adequacy, with the odds of undertreatment twice as high for minority patients. These findings persist over 1 month of follow-up, highlighting the complexity of these problems.
Gene Modules and Response to Neoadjuvant Chemotherapy in Breast Cancer Subtypes: A Pooled Analysis
Authors: Ignatiadis Michail , Singhal Sandeep K. , Desmedt Christine , Haibe-Kains Benjamin , Criscitiello Carmen , Andre Fabrice , Loi Sherene , Piccart Martine , Michiels Stefan , Sotiriou Christos
Published: April 2012

Purpose

To investigate the association between chemotherapy response and gene expression modules describing important biologic processes and druggable oncogenic pathways in breast cancer (BC) subtypes.

Patients and Methods

We searched for publicly available gene expression studies evaluating anthracycline with or without taxane-based neoadjuvant chemotherapy and identified eight studies with 996 patients. We computed 17 gene modules and calculated odds ratios (ORs) for pathologic complete response (pCR) for one-unit increases in scaled modules with and without adjustment for clinicopathologic characteristics. Added predictive accuracy was evaluated using the area under the receiver operating characteristic curve (AUC) and integrated discrimination index (IDI). We used the false discovery rate (FDR) to adjust for multiple testing.

Results

High immune module scores were associated with increased pCR probability in all BC subtypes. High module scores of chromosomal instability, phosphatase and tensin homolog (PTEN) loss, and E2F3 transcription factor were associated with increased pCR probability in estrogen receptor (ER) –negative/human epidermal growth factor receptor 2 (HER2) –negative and ER-positive/HER2-negative but not in HER2-positive tumors (interactions between HER2 and each of these modules for their association with pCR: P < .05; FDR, 0.17; trend for interaction between HER2 and PTEN). High values of insulin-like growth factor 1 activation module were associated with increased pCR probability only in ER-positive/HER2-negative tumors (interaction between insulin-like growth factor 1 and ER: P = .002; FDR, 0.03). When adding the immune module to clinicopathologic characteristics, we observed substantial increases in predictive accuracy for pCR in the HER2-positive subtype (IDI, 0.093; P = .004; increase in AUC from 0.760 to 0.836).

Conclusion

Different processes and pathways are associated with pCR in different BC subtypes.
A Humanized Pattern of Aromatase Expression Is Associated with Mammary Hyperplasia in Mice
Authors: Zhao Hong , Pearson Elizabeth K. , Brooks David C. , Coon V John S. , Chen Dong , Demura Masashi , Zhang Ming , Clevenger Charles V. , Xu Xia , Veenstra Timothy D. , Chatterton Robert T. , DeMayo Francesco J. , Bulun Serdar E.
Published: April 2012

Aromatase is essential for estrogen production and is the target of aromatase inhibitors, the most effective endocrine treatment for postmenopausal breast cancer. Peripheral tissues in women, including the breast, express aromatase via alternative promoters. Female mice lack the promoters that drive aromatase expression in peripheral tissues; thus, we generated a transgenic humanized aromatase (Aromhum) mouse line containing a single copy of the human aromatase gene to study the link between aromatase expression in mammary adipose tissue and breast pathology. Aromhum mice expressed human aromatase, driven by the proximal human promoters II and I.3 and the distal promoter I.4, in breast adipose fibroblasts and myoepithelial cells. Estrogen levels in the breast tissue of Aromhum mice were higher than in wild-type mice, whereas circulating levels were similar. Aromhum mice exhibited accelerated mammary duct elongation at puberty and an increased incidence of lobuloalveolar breast hyperplasia associated with increased signal transducer and activator of transcription-5 phosphorylation at 24 and 64 wk. Hyperplastic epithelial cells showed remarkably increased proliferative activity. Thus, we demonstrated that the human aromatase gene can be expressed via its native promoters in a wide variety of mouse tissues and in a distribution pattern nearly identical to that of humans. Locally increased tissue levels, but not circulating levels, of estrogen appeared to exert hyperplastic effects on the mammary gland. This novel mouse model will be valuable for developing tissue-specific aromatase inhibition strategies.