bluuebunny/crossref_metadata_2025 huggingface dataset:
Vibrio cholerae FeoA, FeoB, and FeoC Interact To Form a Complex
Authors: Stevenson Begoña , Wyckoff Elizabeth E. , Payne Shelley M.
Published: February 2016

Feo is the major ferrous iron transport system in prokaryotes. Despite having been discovered over 25 years ago and found to be widely distributed among bacteria, Feo is poorly understood, as its structure and mechanism of iron transport have not been determined. The
feo
operon in
Vibrio cholerae
is made up of three genes, encoding the FeoA, FeoB, and FeoC proteins, which are all required for Feo system function. FeoA and FeoC are both small cytoplasmic proteins, and their function remains unclear. FeoB, which is thought to function as a ferrous iron permease, is a large integral membrane protein made up of an N-terminal GTPase domain and a C-terminal membrane-spanning region. To date, structural studies of FeoB have been carried out using a truncated form of the protein encompassing only the N-terminal GTPase region. In this report, we show that full-length FeoB forms higher-order complexes when cross-linked
in vivo
in
V. cholerae
. Our analysis of these complexes revealed that FeoB can simultaneously associate with both FeoA and FeoC to form a large complex, an observation that has not been reported previously. We demonstrate that interactions between FeoB and FeoA, but not between FeoB and FeoC, are required for complex formation. Additionally, we identify amino acid residues in the GTPase region of FeoB that are required for function of the Feo system and for complex formation. These observations suggest that this large Feo complex may be the active form of Feo that is used for ferrous iron transport.

IMPORTANCE
The Feo system is the major route for ferrous iron transport in bacteria. In this work, the
Vibrio cholerae
Feo proteins, FeoA, FeoB, and FeoC, are shown to interact to form a large inner membrane complex
in vivo
. This is the first report showing an interaction among all three Feo proteins. It is also determined that FeoA, but not FeoC, is required for Feo complex assembly.
Colanic Acid Intermediates Prevent
De Novo
Shape Recovery of Escherichia coli Spheroplasts, Calling into Question Biological Roles Previously Attributed to Colanic Acid
Authors: Ranjit Dev K. , Young Kevin D.
Published: February 2016

After losing their protective peptidoglycan, bacterial spheroplasts can resynthesize a cell wall to recreate their normal shape. In
Escherichia coli
, this process requires the Rcs response. In its absence, spheroplasts do not revert to rod shapes but instead form enlarged spheroids and lyse. Here, we investigated the reason for this Rcs requirement. Rcs-deficient spheroids exhibited breaks and bulges in their periplasmic spaces and failed to synthesize a complete peptidoglycan cell wall, indicating that the bacterial envelope was defective. To determine the Rcs-dependent gene(s) required for shape recovery, we tested spheroplasts lacking selected RcsB-regulated genes and found that colanic acid (CA) biosynthesis appeared to be involved. Surprisingly, though, extracellular CA was not required for recovery. Instead, lysis was caused by mutations that interrupted CA biosynthesis downstream of the initial glycosyl transferase, WcaJ. Deleting
wcaJ
prevented lysis of spheroplasts lacking ensuing steps in the pathway, and providing WcaJ in
trans
to a mutant lacking the entire CA operon triggered spheroplast enlargement and lysis. Thus, CA is not required for spheroplast recovery. Instead, CA intermediates accumulate as dead-end products which inhibit recovery of wall-less cells. The results strongly imply that CA may not be required for the survival
E. coli
L-forms. More broadly, these findings mandate that previous conclusions about the role of colanic acid in biofilm formation or virulence must be reevaluated.

IMPORTANCE
Wall-less bacteria can resynthesize their walls and recreate a normal shape, which in
Escherichia coli
requires the Rcs response. While attempting to identify the Rcs-dependent gene required for shape recovery, we found that colanic acid (CA) biosynthesis appeared to be involved. Surprisingly, though, cell death was caused by mutations that interrupted CA biosynthesis downstream of the initial step in the pathway, creating dead-end compounds that inhibited recovery of wall-less cells. When testing for the biological role of CA, most previous experiments used mutants that would accumulate these deadly intermediates, meaning that all prior conclusions must be reexamined to determine if the results were caused by these lethal side effects instead of accurately reflecting the biological purpose of CA itself.
The Composition of the Cell Envelope Affects Conjugation in Bacillus subtilis
Authors: Johnson Christopher M. , Grossman Alan D.
Published: February 2016

Conjugation in bacteria is the contact-dependent transfer of DNA from one cell to another via donor-encoded conjugation machinery. It is a major type of horizontal gene transfer between bacteria. Conjugation of the integrative and conjugative element ICEBs1intoBacillus subtilisis affected by the composition of phospholipids in the cell membranes of the donor and recipient. We found that reduction (or elimination) of lysyl-phosphatidylglycerol caused by loss ofmprFcaused a decrease in conjugation efficiency. Conversely, alterations that caused an increase in lysyl-phosphatidylglycerol, including loss ofugtPor overproduction ofmprF, caused an increase in conjugation efficiency. In addition, we found that mutations that alter production of other phospholipids, e.g., loss ofclsAandyfnI, also affected conjugation, apparently without substantively altering levels of lysyl-phosphatidylglycerol, indicating that there are multiple pathways by which changes to the cell envelope affect conjugation. We found that the contribution ofmprFto conjugation was affected by the chemical environment. Wild-type cells were generally more responsive to addition of anions that enhanced conjugation, whereasmprFmutant cells were more sensitive to combinations of anions that inhibited conjugation at pH 7. Our results indicate thatmprFand lysyl-phosphatidylglycerol allow cells to maintain relatively consistent conjugation efficiencies under a variety of ionic conditions.

IMPORTANCEHorizontal gene transfer is a driving force in microbial evolution, enabling cells that receive DNA to acquire new genes and phenotypes. Conjugation, the contact-dependent transfer of DNA from a donor to a recipient by a donor-encoded secretion machine, is a prevalent type of horizontal gene transfer. Although critically important, it is not well understood how the recipient influences the success of conjugation. We found that the composition of phospholipids in the membranes of donors and recipients influences the success of transfer of the integrative and conjugative element ICEBs1inBacillus subtilis. Specifically, the presence of lysyl-phosphatidylglycerol enables relatively constant conjugation efficiencies in a range of diverse chemical environments.
Vitamin D deficiency mimicking chronic tension-type headache in children
Authors: Prakash Sanjay , Makwana Prayag , Rathore Chaturbhuj
Published: February 2016

Headache, musculoskeletal pain and vitamin D deficiency, with possible inter-relationship, are common in the general population. We report cases of three premenarchal girls presenting with chronic tension-type headache and generalised body pain. The patients did not show any response to conventional therapy for tension headache. Investigations showed a severe vitamin D deficiency and biochemical osteomalacia in all three patients. The headaches and musculoskeletal pain responded markedly to vitamin D therapy. We suggest that musculoskeletal pain and headache together in a patient may be part of a single symptom complex, with vitamin D deficiency being the possible cause.
Iodide mumps following fistulogram in a haemodialysis patient
Authors: Ghosh Raktim K , Somasundaram Mey , Ravakhah Keyvan
Published: February 2016

Iodide mumps, or contrast-induced acute sialadenitis, is characterised by rapid, painless enlargement of the salivary glands, following the use of iodinated contrast dye. The underlying mechanism of this adverse reaction is not completely understood. It could be due to an idiosyncratic reaction or related to deposition of iodide in the ductal systems of the salivary glands causing blockage and inflammation. With increasing renal dysfunction, the elimination half-life of the iodine-containing contrast dye gets prolonged. The course of iodine-induced sialadenitis is usually benign, and rapid resolution of symptoms is expected without definite treatment. The symptomatic management includes treatment with a parenteral non-steroidal anti-inflammatory drug (NSAID), steroids and dialysis. However, the role of steroids has been found to be controversial in previously published case reports. Pancreatic mumps and transient thyroid dysfunction were also reported in patients following iodinated contrast administration; the aetiology of this is thought to be similar to iodide-induced sialadenitis.
Are there three main subgroups within the patellofemoral pain population? A detailed characterisation study of 127 patients to help develop targeted intervention (TIPPs)
Authors: Selfe James , Janssen Jessie , Callaghan Michael , Witvrouw Erik , Sutton Chris , Richards Jim , Stokes Maria , Martin Denis , Dixon John , Hogarth Russell , Baltzopoulos Vasilios , Ritchie Elizabeth , Arden Nigel , Dey Paola
Published: February 2016

Background

Current multimodal approaches for the management of non-specific patellofemoral pain are not optimal, however, targeted intervention for subgroups could improve patient outcomes. This study explores whether subgrouping of non-specific patellofemoral pain patients, using a series of low cost simple clinical tests, is possible.

Method

The exclusivity and clinical importance of potential subgroups was assessed by applying à priori test thresholds (1 SD) from seven clinical tests in a sample of adult patients with non-specific patellofemoral pain. Hierarchical clustering and latent profile analysis, were used to gain additional insights into subgroups using data from the same clinical tests.

Results

130 participants were recruited, 127 had complete data: 84 (66%) female, mean age 26 years (SD 5.7) and mean body mass index 25.4 (SD 5.83), median (IQR) time between onset of pain and assessment was 24 (7–60) months. Potential subgroups defined by the à priori test thresholds were not mutually exclusive and patients frequently fell into multiple subgroups. Using hierarchical clustering and latent profile analysis three subgroups were identified using 6 of the 7 clinical tests. These subgroups were given the following nomenclature: (1) ‘strong’, (2) ‘weak and tighter’ and (3) ‘weak and pronated foot’.

Conclusions

We conclude that three subgroups of patellofemoral patients may exist based on the results of six clinical tests which are feasible to perform in routine clinical practice. Further research is needed to validate these findings in other data sets and, if supported by external validation, to see if targeted interventions for these subgroups improve patient outcomes.
Return to work after knee replacement: a qualitative study of patient experiences
Authors: Bardgett Michelle , Lally Joanne , Malviya Ajay , Deehan David
Published: February 2016

Objective

An increasing number of patients in the working population are undergoing total knee replacement (TKR) for end-stage osteoarthritis. The timing and success of return to work is becoming increasingly important for this group of patients with social and economic implications for patients, employers and society. There is limited understanding of the patient variables that determine the ability to return to work. Our objective was (from the patient's perspective) to gain an insight into the factors influencing return to work following knee replacement.

Setting and participants

This qualitative study was undertaken in a secondary-care setting in a large teaching hospital in the north of England. Semistructured interviews were carried out with 10 patients regarding their experiences of returning to work following TKR.

Outcomes

Interviews were transcribed and analysed using a qualitative thematic approach to identify the factors influencing return to work from the patient's perspective.

Results

Three themes were identified that influenced the process of return to work, from the patient's perspective. These were delays in surgical intervention, limited and often inconsistent advice from healthcare professionals regarding return to work, and finally the absence of rehabilitation to optimise patient's recovery and facilitate return to work.

Conclusions

There is currently no consistent process to optimise return to work for patients of working age after TKR. The impact of delayed surgical intervention, limited advice regarding return to work, and a lack of work-focused rehabilitation, all contribute to potential delays in successful return to work. There is a need to change the focus of healthcare provision for this cohort of patients, and provide a tailored healthcare intervention to optimise patient outcomes.
A multinational cross-sectional survey of the management of patient medication adherence by European healthcare professionals
Authors: Clyne Wendy , Mshelia Comfort , McLachlan Sarah , Jones Peter , de Geest Sabina , Ruppar Todd , Siebens Kaat , Dobbels Fabienne , Kardas Przemyslaw
Published: February 2016

Objectives

To examine which interventions healthcare professionals use to support patients with taking medicines and their perceptions about the effectiveness of those actions.

Design

Cross-sectional multinational study.

Setting

Online survey in Austria, Belgium, England, France, Germany, Hungary, The Netherlands, Poland, Portugal and Switzerland.

Participants

A total of 3196 healthcare professionals comprising doctors (855), nurses (1047) and pharmacists (1294) currently registered and practising in primary care and community settings.

Main outcome measures

Primary outcome: Responses to the question ‘I ask patients if they have missed any doses of their medication’ for each profession and in each country.

Secondary outcome: Responses to 50 items concerning healthcare professional behaviour to support patients with medication-taking for each profession and in each country.

Results

Approximately half of the healthcare professionals in the survey ask patients with long-term conditions whether they have missed any doses of their medication on a regular basis. Pharmacists persistently report that they intervene less than the other two professions to support patients with medicines. No country effects were found for the primary outcome.

Conclusions

Healthcare professionals in Europe are limited in the extent to which they intervene to assist patients having long-term conditions with medication adherence. This represents a missed opportunity to support people with prescribed treatment. These conclusions are based on the largest international survey to date of healthcare professionals’ management of medication adherence.
Continuous caudal epidural analgesia for perioperative pain control after bilateral mastectomy in a mare
Authors: Rodrigo‐Mocholi Diego , Steblaj Barbara , Vlaminck Lieven , Gasthuys Frank , Schauvliege Stijn
Published: February 2016

An epidural catheter was used to provide perioperative analgesia as part of a multimodal balanced anaesthesia and analgesia in a mare undergoing a bilateral mastectomy. Despite development of severe hypoxaemia during anaesthesia, recovery from anaesthesia was uneventful. Oral administration of a NSAID combined with administration of xylazine and morphine by an epidural catheter resulted in adequate postoperative pain relief, based on assessment of physiological parameters and behaviour. Neither complications nor side effects were observed during hospitalisation.
Phenology, dichogamy, and floral synchronization in a northern red oak (Quercus rubra) seed orchard
Authors: Alexander Lisa W. , Woeste Keith E.
Published: February 2016

We developed a novel scoring system to assess spring phenology in a northern red oak (Quercus rubra L.) clonal seed orchard. The system was used to score from 304 to 364 ramets for three reproductive seasons and to place clones into early, intermediate, and late phenology classes. Although the absolute number of clones in each phenological class changed from year to year, the overall order of clonal flowering was highly stable (rs = 0.67, p < 0.001). Early-flowering clones flowered significantly longer than later flowering clones in all 3 years. Dichogamy was present in the orchard, with male flowers of a clone emerging from 1.4 to 3.0 d sooner than its female flowers. Mean dichogamy values for individual clones ranged from 0.0 to 4.9 (± 1.3) d. Year strongly influenced a clone’s dichogamy value (F = 6.0, p = 0.004), whereas genotype had no influence. The mean overall phenological synchronicity for the 3 years of observations was 0.30 ± 0.01 or about 30% overlap between the time when females were receptive and males were shedding pollen. This study represents the first effort to quantify phenology in an artificial population of northern red oak, and it provides a snapshot of the current relationship between temperature, phenology, and floral synchronization.
Survey of Obstetrics and Gynecology Residents Regarding Pneumococcal Vaccination in Pregnancy: Education, Knowledge, and Barriers to Vaccination
Authors: Fay Emily E. , Hoppe Kara K. , Schulkin Jay , Eckert Linda O.
Published: February 2016

Objective.The 23-valent pneumococcal vaccine is recommended for adults over 65 years of age and younger adults with certain medical conditions. The Centers for Disease Control and Prevention (CDC) state insufficient evidence to recommend routine pneumococcal vaccination during pregnancy, but the vaccine is indicated for pregnant women with certain medical conditions. We designed this project to gauge obstetrics and gynecology (OB/GYN) resident knowledge of maternal pneumococcal vaccination.Methods.We administered a 22-question survey to OB/GYN residents about maternal pneumococcal vaccination. We performed descriptive analysis for each question.Results.238 OB/GYN residents responded. Overall, 69.3% of residents reported receiving vaccination education and 86.0% reported having ready access to vaccine guidelines and safety data. Most residents knew that asplenia (78.2%), pulmonary disease (77.3%), and HIV/AIDS (69.4%) are indications for vaccination but less knew that cardiovascular disease (45.0%), diabetes (35.8%), asthma (42.8%), nephrotic syndrome (19.7%), and renal failure (33.6%) are also indications for vaccination.Conclusion. OB/GYN residents are taught about vaccines and have ready access to vaccine guidelines and safety data. However, knowledge of indications for pneumococcal vaccination in pregnancy is lacking. Likely, the opportunity to vaccinate at-risk pregnant patients is being missed.
Optical Band Gap and Thermal Diffusivity of Polypyrrole-Nanoparticles Decorated Reduced Graphene Oxide Nanocomposite Layer
Authors: Sadrolhosseini Amir Reza , Abdul Rashid Suraya , Noor A. S. M. , Kharazmi Alireza , Lim H. N. , Mahdi Mohd. Adzir
Published: February 2016

A polypyrrole-nanoparticles reduced graphene oxide nanocomposite layer was prepared using electrochemical method. The prepared samples were characterized using Fourier transform infrared spectroscopy, field emission scanning electron microscopy, and UV-visible spectroscopy. The band gap of nanocomposite layers was calculated from UV-visible spectra and the thermal diffusivity of layers was measured using a photoacoustic technique. As experimental results, the optical band gap was in the range between 3.580 eV and 3.853 eV, and thermal diffusivity was increased with increasing the layer thickness from 2.873 cm2/s to 12.446 cm2/s.
Low Density Lipoprotein Receptor Related Proteins as Regulators of Neural Stem and Progenitor Cell Function
Authors: Auderset Loic , Landowski Lila M. , Foa Lisa , Young Kaylene M.
Published: February 2016

The central nervous system (CNS) is a highly organised structure. Many signalling systems work in concert to ensure that neural stem cells are appropriately directed to generate progenitor cells, which in turn mature into functional cell types including projection neurons, interneurons, astrocytes, and oligodendrocytes. Herein we explore the role of the low density lipoprotein (LDL) receptor family, in particular family members LRP1 and LRP2, in regulating the behaviour of neural stem and progenitor cells during development and adulthood. The ability of LRP1 and LRP2 to bind a diverse and extensive range of ligands, regulate ligand endocytosis, recruit nonreceptor tyrosine kinases for direct signal transduction and signal in conjunction with other receptors, enables them to modulate many crucial neural cell functions.
De NovoTrisomy 1q10q23.3 Mosaicism Causes Microcephaly, Severe Developmental Delay, and Facial Dysmorphic Features but No Cardiac Anomalies
Authors: Lo-A-Njoe Shirley , van der Veken Lars T. , Vermont Clementien , Rafael-Croes Louise , Keizer Vincent , Hochstenbach Ron , Knoers Nine , van Haelst Mieke M.
Published: January 2016

Proximal duplications of chromosome 1q are rare chromosomal abnormalities. Most patients with this condition present with neurological, urogenital, and congenital heart disease and short life expectancy. Mosaicism for trisomy 1q10q23.3 has only been reported once in the literature. Here we discuss a second case: a girl with a postnatal diagnosis of ade novopure mosaic trisomy 1q1023.3 who has no urogenital or cardiac anomalies.
On Characterization of Rough Type-2 Fuzzy Sets
Authors: Zhao Tao , Wei Zhenbo
Published: February 2016

Rough sets theory and fuzzy sets theory are important mathematical tools to deal with uncertainties. Rough fuzzy sets and fuzzy rough sets as generalizations of rough sets have been introduced. Type-2 fuzzy set provides additional degree of freedom, which makes it possible to directly handle high uncertainties. In this paper, the rough type-2 fuzzy set model is proposed by combining the rough set theory with the type-2 fuzzy set theory. The rough type-2 fuzzy approximation operators induced from the Pawlak approximation space are defined. The rough approximations of a type-2 fuzzy set in the generalized Pawlak approximation space are also introduced. Some basic properties of the rough type-2 fuzzy approximation operators and the generalized rough type-2 fuzzy approximation operators are discussed. The connections between special crisp binary relations and generalized rough type-2 fuzzy approximation operators are further examined. The axiomatic characterization of generalized rough type-2 fuzzy approximation operators is also presented. Finally, the attribute reduction of type-2 fuzzy information systems is investigated.
A Study on Defect Identification of Planetary Gearbox under Large Speed Oscillation
Authors: Jiang Xingxing , Li Shunming , Wang Qian
Published: January 2016

Rotational speed of a reference shaft is the key information for planetary gearbox condition monitoring under nonstationary conditions. As the time-variant speed and load of planetary gearboxes result in time-variant characteristic frequencies as well as vibration magnitudes, the conventional methods tracking time-frequency ridge perform a poor robustness, especially for large speed variations. In this paper, two schemes, time-frequency ridge fusion and logarithm transformation, are proposed to track the targeted ridge curve reliably. Meanwhile, the identified ridge curve by logarithm scheme can be further refined by the time-frequency ridge fusion scheme. Hence, a procedure involving the proposed ridge estimation methods is presented to diagnose the planetary gearbox defects. Two simulation signals and a vibration signal collected from a planetary gearbox in practical engineering (provided by the conference on condition monitoring of machinery in nonstationary operations (CMMNO)) are used to verify the proposed methods. It is validated that the proposed methods can well-track the targeted ridge curve compared with two conventional methods. As a result, the characteristic frequency of each component in the planetary gearbox is clearly demonstrated and the inner race defect of one of the planet bearings is successfully discovered in the order spectrum depending on the derived expression of planet bearing fault frequency.
Infestation of Glycaspis brimblecombei Moore on Thirteen Eucalyptus Species and Their Relationship with the Chemical Composition of Essential Oils
Authors: Lucia Alejandro , Naspi Cecilia , Zerba Eduardo , Masuh Héctor
Published: February 2016

Glycaspis brimblecombei is a pest insect that affects Eucalyptus genus and was firstly detected in Argentina in 2005. The main objective of this study is to determine the correlation between the level of infestation and chemical composition of essential oils extract. In an experimental plantation of 13 Eucalyptus species, the natural presence of the psyllid in the adaxial and abaxial faces of the leaves was determined and the mean number of individuals per species was calculated. The essential oils were extracted by hydrodistillation and analyzed for their chemical composition by gas chromatography-mass spectrometry. The results showed that 7 out of 13 species of Eucalyptus were not affected by G. brimblecombei: E. dunnii, E. globulus maidenii, E. globulus ssp. globulus, E. viminalis, E. cinerea, E. sideroxylon, and E. gunnii. The most affected Eucalyptus species were E. tereticornis and E. camaldulensis whereas the infestation in E. grandis × E. tereticornis and E. grandis × E. camaldulensis was intermediate. E. saligna and E. grandis were the least affected species. The relative concentrations of the compounds 1,8-cineole and α- and β-phellandrene in the essential oils are highly correlated to the rate of infestation with G. brimblecombei.
A Case of Brain Abscess Caused by Medication-Related Osteonecrosis of the Jaw
Authors: Yamagata Kenji , Nagai Hiroki , Baba Osamu , Uchida Fumihiko , Kanno Naomi , Hasegawa Shogo , Yanagawa Toru , Bukawa Hiroki
Published: February 2016

Reports of brain abscesses caused by medication-related osteonecrosis of the jaw (MRONJ) are very rare. We here present the case of a 76-year-old man with terminal-stage prostatic carcinoma and a brain abscess caused by MRONJ at the maxilla. The patient had been treated with zoledronic acid and denosumab for bone metastasis. For the brain abscess, an antibiotic regimen based on ceftriaxone and metronidazole and a sequestrectomy contributed to a successful outcome. In the case of maxillary MRONJ extending to the maxillary sinus, active resection of the infected bone should be considered to prevent the spread of the infection beyond the maxillary sinus, into the ethmoid sinus, and into the brain.
General Results for the Transmuted Family of Distributions and New Models
Authors: Bourguignon Marcelo , Ghosh Indranil , Cordeiro Gauss M.
Published: January 2016

The transmuted family of distributions has been receiving increased attention over the last few years. For a baselineGdistribution, we derive a simple representation for the transmuted-Gfamily density function as a linear mixture of theGand exponentiated-Gdensities. We investigate the asymptotes and shapes and obtain explicit expressions for the ordinary and incomplete moments, quantile and generating functions, mean deviations, Rényi and Shannon entropies, and order statistics and their moments. We estimate the model parameters of the family by the method of maximum likelihood. We prove empirically the flexibility of the proposed model by means of an application to a real data set.
Interpretation of MUSIC for Location Detecting of Small Inhomogeneities Surrounded by Random Scatterers
Authors: Park Won-Kwang
Published: February 2016

We consider the MUltiple SIgnal Classification (MUSIC) algorithm for identifying the locations of small electromagnetic inhomogeneities surrounded by random scatterers. For this purpose, we rigorously analyze the structure of MUSIC-type imaging function by establishing a relationship with zero-order Bessel function of the first kind. This relationship shows certain properties of the MUSIC algorithm, explains some unexplained phenomena, and provides a method for improvements.
Inhibition of MUC1-C Suppresses MYC Expression and Attenuates Malignant Growth in KRAS Mutant Lung Adenocarcinomas
Authors: Bouillez Audrey , Rajabi Hasan , Pitroda Sean , Jin Caining , Alam Maroof , Kharbanda Akriti , Tagde Ashujit , Wong Kwok-Kin , Kufe Donald
Published: February 2016

Dysregulation of MYC expression is a hallmark of cancer, but the development of agents that target MYC has remained challenging. The oncogenic MUC1-C transmembrane protein is, like MYC, aberrantly expressed in diverse human cancers. The present studies demonstrate that MUC1-C induces MYC expression in KRAS mutant non–small cell lung cancer (NSCLC) cells, an effect that can be suppressed by targeting MUC1-C via shRNA silencing, CRISPR editing, or pharmacologic inhibition with GO-203. MUC1-C activated the WNT/β-catenin (CTNNB1) pathway and promoted occupancy of MUC1-C/β-catenin/TCF4 complexes on the MYC promoter. MUC1-C also promoted the recruitment of the p300 histone acetylase (EP300) and, in turn, induced histone H3 acetylation and activation of MYC gene transcription. We also show that targeting MUC1-C decreased the expression of key MYC target genes essential for the growth and survival of NSCLC cells, such as TERT and CDK4. Based on these results, we found that the combination of GO-203 and the BET bromodomain inhibitor JQ1, which targets MYC transcription, synergistically suppressed MYC expression and cell survival in vitro as well as tumor xenograft growth. Furthermore, MUC1 expression significantly correlated with that of MYC and its target genes in human KRAS mutant NSCLC tumors. Taken together, these findings suggest a therapeutic approach for targeting MYC-dependent cancers and provide the framework for the ongoing clinical studies addressing the efficacy of MUC1-C inhibition in solid tumors. Cancer Res; 76(6); 1538–48. ©2016 AACR.
The Cancer Stem Cell Fraction in Hierarchically Organized Tumors Can Be Estimated Using Mathematical Modeling and Patient-Specific Treatment Trajectories
Authors: Werner Benjamin , Scott Jacob G. , Sottoriva Andrea , Anderson Alexander R.A. , Traulsen Arne , Altrock Philipp M.
Published: February 2016

Many tumors are hierarchically organized and driven by a subpopulation of tumor-initiating cells (TIC), or cancer stem cells. TICs are uniquely capable of recapitulating the tumor and are thought to be highly resistant to radio- and chemotherapy. Macroscopic patterns of tumor expansion before treatment and tumor regression during treatment are tied to the dynamics of TICs. Until now, the quantitative information about the fraction of TICs from macroscopic tumor burden trajectories could not be inferred. In this study, we generated a quantitative method based on a mathematical model that describes hierarchically organized tumor dynamics and patient-derived tumor burden information. The method identifies two characteristic equilibrium TIC regimes during expansion and regression. We show that tumor expansion and regression curves can be leveraged to infer estimates of the TIC fraction in individual patients at detection and after continued therapy. Furthermore, our method is parameter-free; it solely requires the knowledge of a patient's tumor burden over multiple time points to reveal microscopic properties of the malignancy. We demonstrate proof of concept in the case of chronic myeloid leukemia (CML), wherein our model recapitulated the clinical history of the disease in two independent patient cohorts. On the basis of patient-specific treatment responses in CML, we predict that after one year of targeted treatment, the fraction of TICs increases 100-fold and continues to increase up to 1,000-fold after 5 years of treatment. Our novel framework may significantly influence the implementation of personalized treatment strategies and has the potential for rapid translation into the clinic. Cancer Res; 76(7); 1705–13. ©2016 AACR.
Micrometastasis Volume in Lymph Nodes Determines Disease Recurrence Rate of Stage II Colorectal Cancer: A Prospective Multicenter Trial
Authors: Yamamoto Hirofumi , Murata Kohei , Fukunaga Mutsumi , Ohnishi Tadashi , Noura Shingo , Miyake Yasuhiro , Kato Takeshi , Ohtsuka Masahisa , Nakamura Yurika , Takemasa Ichiro , Mizushima Tsunekazu , Ikeda Masataka , Ohue Masayuki , Sekimoto Mitsugu , Nezu Riichiro , Matsuura Nariaki , Monden Morito , Doki Yuichiro , Mori Masaki
Published: February 2016

Purpose: We reported in a retrospective study that the presence of micrometastasis in lymph nodes, when assessed by carcinoembryonic antigen (CEA)-specific RT-PCR, is a significant prognostic factor in stage II colorectal cancer. The aim of this study was to clarify the clinical value of micrometastasis in a prospective multicenter trial.

Experimental Design: From November 2001 to December 2005, a total of 419 colorectal cancer cases were preoperatively registered at a central data center. Of them, 315 node-negative stage II colorectal cancer cases were enrolled. After RNA quality check, 304 colorectal cancer cases were analyzed for CEA mRNA in lymph nodes by both conventional RT-PCR (a band method) and quantitative RT-PCR. Long-term prognosis of the patients was determined by each method.

Results: A positive band for CEA mRNA was detected in 73 (24.0%) of 304 patients. Postoperative adjuvant chemotherapy was applied in 31 CEA band-positive cases with an oral 5-fluorouracil derivative HCFU (1-hexylcarbamoyl-5-fluorouracil) for 1 year, whereas chemotherapy was not administered to CEA band-negative group. Multivariate Cox regression analyses revealed that a high micrometastasis volume (high MMV, n = 95) was an independent poor prognostic factor for 5-year disease-free survival (DFS; P = 0.001) and 5-year overall survival (OS; P = 0.016).

Conclusions: This prospective clinical trial demonstrates that micrometastasis volume is a useful marker in identifying patients who are at high or low risk for recurrence of stage II colorectal cancer. Clin Cancer Res; 22(13); 3201–8. ©2016 AACR.
Mutations in TSC1, TSC2, and MTOR Are Associated with Response to Rapalogs in Patients with Metastatic Renal Cell Carcinoma
Authors: Kwiatkowski David J. , Choueiri Toni K. , Fay André P. , Rini Brian I. , Thorner Aaron R. , de Velasco Guillermo , Tyburczy Magdalena E. , Hamieh Lana , Albiges Laurence , Agarwal Neeraj , Ho Thai H. , Song Jiaxi , Pignon Jean-Christophe , Barrios Pablo M. , Michaelson M. Dror , Van Allen Eliezer M. , Krajewski Katherine M. , Porta Camillo , Pal Sumanta Kumar , Bellmunt Joaquim , McDermott David F. , Heng Daniel Y.C. , Gray Kathryn P. , Signoretti Sabina
Published: February 2016

Purpose: We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC).

Experimental Design: We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next-generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for 6 months or longer. Nonresponders were defined as those with disease progression during the first 3 months of therapy. Fisher exact test assessed the association between mutation status in mTOR pathway genes and treatment response.

Results: Mutations in MTOR, TSC1, or TSC2 were more common in responders, 12 (28%) of 43, than nonresponders, 4 (11%) of 36 (P = 0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than nonresponders, 2(6%), (P = 0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1, or TSC2 compared with 4 (11%) of 36 nonresponders (P = 0.03). Eight additional non-mTOR pathway genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response.

Conclusions: In this cohort of mRCC patients, mutations in MTOR, TSC1, or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (24 of 43, 56%) had no mTOR pathway mutation identified. Clin Cancer Res; 22(10); 2445–52. ©2016 AACR.

See related commentary by Voss and Hsieh, p. 2320
Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress
Authors: Wang Chun Yan , Guo Su Tang , Wang Jia Yu , Liu Fen , Zhang Yuan Yuan , Yari Hamed , Yan Xu Guang , Jin Lei , Zhang Xu Dong , Jiang Chen Chen
Published: February 2016

Oncogenic mutations of KRAS pose a great challenge in the treatment of colorectal cancer. Here we report that mutant KRAS colon cancer cells are nevertheless more susceptible to apoptosis induced by the HSP90 inhibitor AUY922 than those carrying wild-type KRAS. Although AUY922 inhibited HSP90 activity with comparable potency in colon cancer cells irrespective of their KRAS mutational statuses, those with mutant KRAS were markedly more sensitive to AUY922-induced apoptosis. This was associated with upregulation of the BH3-only proteins Bim, Bik, and PUMA. However, only Bim appeared essential, in that knockdown of Bim abolished, whereas knockdown of Bik or PUMA only moderately attenuated apoptosis induced by AUY922. Mechanistic investigations revealed that endoplasmic reticulum (ER) stress was responsible for AUY922-induced upregulation of Bim, which was inhibited by a chemical chaperone or overexpression of GRP78. Conversely, siRNA knockdown of GRP78 or XBP-1 enhanced AUY922-induced apoptosis. Remarkably, AUY922 inhibited the growth of mutant KRAS colon cancer xenografts through activation of Bim that was similarly associated with ER stress. Taken together, these results suggest that AUY922 is a promising drug in the treatment of mutant KRAS colon cancers, and the agents that enhance the apoptosis-inducing potential of Bim may be useful to improve the therapeutic efficacy. Mol Cancer Ther; 15(3); 448–59. ©2016 AACR.
The Case for a Pre-Cancer Genome Atlas (PCGA)
Authors: Campbell Joshua D. , Mazzilli Sarah A. , Reid Mary E. , Dhillon Samjot S. , Platero Suso , Beane Jennifer , Spira Avrum E.
Published: February 2016

Understanding the earliest molecular and cellular events associated with cancer initiation remains a key bottleneck to transforming our approach to cancer prevention and detection. While TCGA has provided unprecedented insights into the genomic events associated with advanced stage cancer, there have been few studies comprehensively profiling premalignant and early-stage disease or elucidating the role of the microenvironment in premalignancy and tumor initiation. In this article, we make a call for development of a “Pre-Cancer Genome Atlas (PCGA),” a concerted initiative to characterize the molecular alterations in premalignant lesions and the corresponding changes in the microenvironment associated with progression to invasive carcinoma. This initiative will require a multicenter coordinated effort to comprehensively profile (cellular and molecular) premalignant lesions and their corresponding “field of injury” collected longitudinally as the lesion progresses towards or regresses from frank malignancy across multiple tumor types. Genomic characterization of alterations in premalignant lesions and their microenvironment, for both bulk tissue and single cells, will enable development of biomarkers for early detection and risk stratification as well as allow for the development of novel targeted cancer interception strategies. The multi-institutional and multidisciplinary collaborative “big-data” effort underlying the PCGA will help usher in a new era of precision medicine for cancer detection and prevention. Cancer Prev Res; 9(2); 119–24. ©2016 AACR.
Targeting ONOO-/HMGB1/MMP-9 Signaling Cascades: Potential for Drug Development from Chinese Medicine to Attenuate Ischemic Brain Injury and Hemorrhagic Transformation Induced by Thrombolytic Treatment
Authors: Chen Hansen , Guan Binghe , Shen Jiangang
Published: February 2016

Stroke is the leading cause of death and disability worldwide, and ischemic stroke accounts for more than 85% of the stroke incidence. Tissue plasminogen activator (t-PA) is the only FDA-approved drug for ischemic stroke treatment with a narrow treatment time window of 4.5 h. Hemorrhagic transformation (HT) is a severe complication of delayed t-PA treatment in ischemic stroke. Thus, it is critically important to develop combination therapies to reduce HT and extend the therapeutic time window of t-PA. Current progress suggests that peroxynitrite (ONOO-)/high-mobility group box 1 protein (HMGB1)/matrix metalloproteinase-9 (MMP-9) signaling cascades could be important for attenuating HT during thrombolytic treatment for acute ischemic stroke. Recently, important progress has been made in seeking for natural compounds from Chinese medicine for reducing ischemic stroke injury, with some of them targeting ONOO-/HMGB1/MMP-9 signaling cascades. Herein, we analyze the roles and interactions of these three targets in mediating HT; subsequently, we summarize the potential compounds from Chinese herbal medicine for attenuating HT and analyze the related targets. Finally, we raise the potential issues to be addressed in further development of these compounds as combination therapy.
Early Vasospasm after Aneurysmal Subarachnoid Hemorrhage Predicts the Occurrence and Severity of Symptomatic Vasospasm and Delayed Cerebral Ischemia
Authors: Jabbarli Ramazan , Reinhard Matthias , Shah Mukesch , Roelz Roland , Niesen Wolf-Dirk , Kaier Klaus , Taschner Christian , Weyerbrock Astrid , Van Velthoven Vera
Published: February 2016

Background: Cerebral vasospasm usually develops several days after subarachnoid hemorrhage (SAH) and is generally acknowledged as a strong outcome predictor. In contrast, much less is known about the nature and eventual consequences of early angiographic vasospasm (EAVS) seen on admission digital subtraction angiography (DSA). Therefore, we aimed at identifying the risk factors and clinical impact of EAVS after SAH. Methods: Five hundred and thirty-one SAH patients with admission DSA performed within 72 h after the bleeding event were selected from a comprehensive database containing all consecutive SAH patients treated at our institution between January 2005 and December 2012. Predictors of EAVS, as well as associations between EAVS and delayed vasospasm-related complications, and unfavorable outcome (defined as modified Rankin scale >3) were evaluated in univariate and multivariate analyses. Results: EAVS was seen on 60 DSAs (11.3%) and was independently correlated with delayed symptomatic vasospasm requiring intra-arterial spasmolysis (OR 5.24, p < 0.0001), angioplasty (OR 2.56, p = 0.015) and repetitive endovascular treatment (OR 4.71, p < 0.0001). EAVS also increased the risk for multiple versus single territorial infarction on the follow-up CT scan(s) (OR 2.04, p = 0.047) and independently predicted unfavorable outcome (OR 2.93, p = 0.008). The presence of radiographic signs suspicious for fibromuscular dysplasia were independently associated with the occurrence of EAVS (OR 2.98, p = 0.026) and the need for repetitive endovascular vasospasm treatment (OR 3.95, p = 0.019). Conclusions: In view of the strong correlation with delayed symptomatic vasospasm and its ischemic complications, EAVS can be considered an alerting signal for severe symptomatic vasospasm. Therefore, more attention should be paid to the presence of EAVS on admission DSA.
Nodular Cutaneous Amyloidosis Resembling a Giant Tumor
Authors: Haverkampf Sonja , Evert Katja , Schröder Josef , Schreml Stephan
Published: February 2016

A 79-year-old man presented with a large tumor on the left side of his head, which had grown over 5 years. Regional lymph nodes were impalpable and computed tomography revealed no signs of bone infiltration. Histology showed that the entire dermis was filled with amorphous eosinophilic material. Immunohistochemistry was negative for cytokeratin, but showed that the dermis and parts of the subcutis were filled with amyloid consisting of immunoglobulin light chains. There were no signs of paraproteinemia or underlying plasmocytoma. In electron microscopy, the typical amyloid fibrils were found. The tumor was completely removed via curettage. At 1-year follow-up, the patient was doing fine with no signs of relapse or systemic disease.
Acute Response to Unilateral Unipolar Electrical Carotid Sinus Stimulation in Patients With Resistant Arterial Hypertension
Authors: Heusser Karsten , Tank Jens , Brinkmann Julia , Menne Jan , Kaufeld Jessica , Linnenweber-Held Silvia , Beige Joachim , Wilhelmi Mathias , Diedrich André , Haller Hermann , Jordan Jens
Published: February 2016

Bilateral bipolar electric carotid sinus stimulation acutely reduced muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in patients with resistant arterial hypertension but is no longer available. The second-generation device uses a smaller unilateral unipolar disk electrode to reduce invasiveness while saving battery life. We hypothesized that the second-generation device acutely lowers BP and MSNA in treatment-resistant hypertensive patients. Eighteen treatment-resistant hypertensive patients (9 women/9 men; 53±11 years; 33±5 kg/m
2
) on stable medications have been included in the study. We monitored finger and brachial BP, heart rate, and MSNA. Without stimulation, BP was 165±31/91±18 mm Hg, heart rate was 75±17 bpm, and MSNA was 48±14 bursts per minute. Acute stimulation with intensities producing side effects that were tolerable in the short term elicited interindividually variable changes in systolic BP (–16.9±15.0 mm Hg; range, 0.0 to −40.8 mm Hg;
P
=0.002), heart rate (−3.6±3.6 bpm;
P
=0.004), and MSNA (−2.0±5.8 bursts per minute;
P
=0.375). Stimulation intensities had to be lowered in 12 patients to avoid side effects at the expense of efficacy (systolic BP, −6.3±7.0 mm Hg; range, 2.8 to −14.5 mm Hg;
P
=0.028 and heart rate, −1.5±2.3 bpm;
P
=0.078; comparison against responses with side effects). Reductions in diastolic BP and MSNA (total activity) were correlated (
r
2
=0.329;
P
=0.025). In our patient cohort, unilateral unipolar electric baroreflex stimulation acutely lowered BP. However, side effects may limit efficacy. The approach should be tested in a controlled comparative study.