bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metabolic Determinants of Sensitivity to Phosphatidylinositol 3-Kinase Pathway Inhibitor in Small-Cell Lung Carcinoma
Authors: Makinoshima Hideki , Umemura Shigeki , Suzuki Ayako , Nakanishi Hiroki , Maruyama Ami , Udagawa Hibiki , Mimaki Sachiyo , Matsumoto Shingo , Niho Seiji , Ishii Genichiro , Tsuboi Masahiro , Ochiai Atsushi , Esumi Hiroyasu , Sasaki Takehiko , Goto Koichi , Tsuchihara Katsuya 
Published: February 2018

Abstract
Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here, we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. Substantial phosphatidyl lipid analysis revealed that a specific phosphatidylinositol (3,4,5)-trisphosphate (PIP3) subspecies lipid product PIP3 (38:4) is predictive in assessing sensitivity to PI3K/mTOR dual inhibitor. Notably, we found that higher amounts of purine-related aqueous metabolites such as hypoxanthine, which are characteristic of SCLC biology, lead to resistance to PI3K pathway inhibition. In addition, the levels of the mRNA encoding hypoxanthine phosphoribosyl transferase 1, a key component of the purine salvage pathway, differed significantly between SCLC cells sensitive or resistant to gedatolisib. Moreover, complementation with purine metabolites could reverse the vulnerability to targeting of the PI3K pathway in SCLC cells normally sensitive to gedatolisib. These results indicate that the resistance mechanism of PI3K pathway inhibitors is mediated by the activation of the purine salvage pathway, supplying purine resource to nucleotide biosynthesis. Metabolomics is a powerful approach for finding novel therapeutic biomarkers in SCLC treatment.
Significance: These findings identify features that determine sensitivity of SCLC to PI3K pathway inhibition and support metabolomics as a tool for finding novel therapeutic biomarkers. Cancer Res; 78(9); 2179–90. ©2018 AACR.
YAP1-Mediated Suppression of USP31 Enhances NFκB Activity to Promote Sarcomagenesis
Authors: Ye Shuai , Lawlor Matthew A. , Rivera-Reyes Adrian , Egolf Shaun , Chor Susan , Pak Koreana , Ciotti Gabrielle E. , Lee Avery C. , Marino Gloria E. , Shah Jennifer , Niedzwicki David , Weber Kristy , Park Paul M.C. , Alam Md. Zahidul , Grazioli Alison , Haldar Malay , Xu Mousheng , Perry Jennifer A. , Qi Jun , Eisinger-Mathason T.S. Karin 
Published: February 2018

AbstractTo date, no consistent oncogenic driver mutations have been identified in most adult soft tissue sarcomas; these tumors are thus generally insensitive to existing targeted therapies. Here we investigated alternate mechanisms underlying sarcomagenesis to identify potential therapeutic interventions. Undifferentiated pleomorphic sarcoma (UPS) is an aggressive tumor frequently found in skeletal muscle where deregulation of the Hippo pathway and aberrant stabilization of its transcriptional effector yes-associated protein 1 (YAP1) increases proliferation and tumorigenesis. However, the downstream mechanisms driving this deregulation are incompletely understood. Using autochthonous mouse models and whole genome analyses, we found that YAP1 was constitutively active in some sarcomas due to epigenetic silencing of its inhibitor angiomotin (AMOT). Epigenetic modulators vorinostat and JQ1 restored AMOT expression and wild-type Hippo pathway signaling, which induced a muscle differentiation program and inhibited sarcomagenesis. YAP1 promoted sarcomagenesis by inhibiting expression of ubiquitin-specific peptidase 31 (USP31), a newly identified upstream negative regulator of NFκB signaling. Combined treatment with epigenetic modulators effectively restored USP31 expression, resulting in decreased NFκB activity. Our findings highlight a key underlying molecular mechanism in UPS and demonstrate the potential impact of an epigenetic approach to sarcoma treatment.Significance: A new link between Hippo pathway signaling, NFκB, and epigenetic reprogramming is highlighted and has the potential for therapeutic intervention in soft tissue sarcomas. Cancer Res; 78(10); 2705–20. ©2018 AACR.
<b>Status and conservation issues of wetland birds in Komaranahalli Lake, Davanagere District, Karnataka, India</b>
Authors: Harisha M. N. , Hosetti B. B. 
Published: February 2018

This study was carried out to assess the status and conservation issues of migratory water birds in Komaranahalli Kere, a lake in Malebennur, Harihar Taluk, Davanagere District from November 2012 to October 2013. The dominant family was Ardeidae represented by 10 species, followed by the Scolopacidae with seven species. The families with lowest representations of one species were Podicipididae, Anhingidae, Rostratulidae and Recurvirostridae. The study revealed that the lake harbors many resident and a few migratory bird species. Among the species recorded five species namely the Black-headed Ibis Threskiornis melanocephalus, Oriental Darter Anhinga melanogaster, Black-tailed Godwit Limosa limosa, Painted Stork Mycteria leucocephala and River Tern Sterna aurantia are Near Threatened. The present study location is also facing tremendous conservation challenges by the impact of anthropogenic alteration of the habitats in and around the lake. Though the lake is highly disturbed, it still provides some potential habitats for a few migratory and several resident water bird species.
<b>An annotated checklist of the herpetofauna of the Rashtrapati Bhawan Estates, New Delhi, India</b>
Authors: Prasad Vishal Kumar , Verma Anjali , Shahabuddin Ghazala 
Published: February 2018

Rashtrapati Bhavan Estates is a large semi-natural area comprising significant patches of secondary forest, cultivation, wetlands and parks in the heart of Delhi, the capital city of India. An inventory of herpetofauna was undertaken from May 15 to July 31, 2015, which revealed four species of amphibians and eight of reptiles. One reptilian species—Striped Keelback—was a new record for the Delhi region. In addition, secondary records of the presence of five snake species were obtained. Given the paucity of published data on natural history of the national capital, this annotated species checklist assumes importance and will be of use for urban planning and conservation.
Vascular Smooth Muscle–Specific Progerin Expression Accelerates Atherosclerosis and Death in a Mouse Model of Hutchinson-Gilford Progeria Syndrome
Authors: Hamczyk Magda R. , Villa-Bellosta Ricardo , Gonzalo Pilar , Andrés-Manzano María J. , Nogales Paula , Bentzon Jacob F. , López-Otín Carlos , Andrés Vicente 
Published: February 2018

Background:
Progerin, an aberrant protein that accumulates with age, causes the rare genetic disease Hutchinson-Gilford progeria syndrome (HGPS). Patients who have HGPS exhibit ubiquitous progerin expression, accelerated aging and atherosclerosis, and die in their early teens, mainly of myocardial infarction or stroke. The mechanisms underlying progerin-induced atherosclerosis remain unexplored, in part, because of the lack of appropriate animal models.

Methods:

We generated an atherosclerosis-prone model of HGPS by crossing apolipoprotein E–deficient (
Apoe
–/–
) mice with
Lmna

G609G/G609G

mice ubiquitously expressing progerin. To induce progerin expression specifically in macrophages or vascular smooth muscle cells (VSMCs), we crossed
Apoe
–/–
Lmna

LCS/LCS

mice with
LysMCre
and
SM22αCre
mice, respectively. Progerin expression was evaluated by polymerase chain reaction and immunofluorescence. Cardiovascular alterations were determined by immunofluorescence and histology in male mice fed normal chow or a high-fat diet. In vivo low-density lipoprotein retention was assessed by intravenous injection of fluorescently labeled human low-density lipoprotein. Cardiac electric defects were evaluated by electrocardiography.

Results:

Apoe
–/–
Lmna

G609G/G609G

mice with ubiquitous progerin expression exhibited a premature aging phenotype that included failure to thrive and shortened survival. In addition, high-fat diet–fed
Apoe
–/–
Lmna

G609G/G609G

mice developed a severe vascular pathology, including medial VSMC loss and lipid retention, adventitial fibrosis, and accelerated atherosclerosis, thus resembling most aspects of cardiovascular disease observed in patients with HGPS. The same vascular alterations were also observed in
Apoe
–/–
Lmna

LCS/LCS

SM22αCre
mice expressing progerin specifically in VSMCs, but not in
Apoe
–/–
Lmna

LCS/LCS

LysMCre
mice with macrophage-specific progerin expression. Moreover,
Apoe
–/–
Lmna

LCS/LCS

SM22αCre
mice had a shortened lifespan despite the lack of any overt aging phenotype. Aortas of ubiquitously and VSMC-specific progerin-expressing mice exhibited increased retention of fluorescently labeled human low-density lipoprotein, and atheromata in both models showed vulnerable plaque features. Immunohistopathological examination indicated that
Apoe
–/–
Lmna

LCS/LCS

SM22αCre
mice, unlike
Apoe
–/–
Lmna

G609G/G609G

mice, die of atherosclerosis-related causes.

Conclusions:
We have generated the first mouse model of progerin-induced atherosclerosis acceleration, and demonstrate that restricting progerin expression to VSMCs is sufficient to accelerate atherosclerosis, trigger plaque vulnerability, and reduce lifespan. Our results identify progerin-induced VSMC death as a major factor triggering atherosclerosis and premature death in HGPS.
Cardiac Rehabilitation Protects Against the Expansion of Abdominal Aortic Aneurysm
Authors: Nakayama Atsuko , Morita Hiroyuki , Nagayama Masatoshi , Hoshina Katsuyuki , Uemura Yukari , Tomoike Hitonobu , Komuro Issei 
Published: February 2018

Background

Virtually no reports on the effects of exercise in patients with a small abdominal aortic aneurysm (
AAA
) exist.

Methods and Results

We conducted a retrospective cohort study on 1515 patients with a small
AAA
before surgery at 2 high‐volume hospitals in Tokyo, Japan, from April 2004 to September 2015. A carefully modified cardiac rehabilitation program without excessive blood pressure elevation during exercise was prescribed to 50 patients with an
AAA
. Using propensity score matching, mortality and clinical outcomes, including
AAA
expansion rate, were compared between 2 groups: rehabilitation group and nonrehabilitation group. The background characteristics of the rehabilitation group (n=49) and the nonrehabilitation group (n=163) were almost identical. The risk for
AAA
repair was much lower in the rehabilitation group after matching (before matching: hazard ratio, 0.43; 95% confidence interval, 0.25–0.72;
P
=0.001; and after matching: hazard ratio, 0.19; 95% confidence interval, 0.07–0.50;
P
<0.001).
AAA
expansion rate was slower in the rehabilitation group (before matching: rehabilitation versus nonrehabilitation group, 2.3±3.7 versus 3.8±3.4 mm/y [
P
=0.008]; after matching: rehabilitation versus nonrehabilitation group, 2.1±3.0 versus 4.5±4.0 mm/y [
P
<0.001]). Elevation of blood pressure during exercise was positively correlated with
AAA
expansion rate after the rehabilitation program (
r
=0.569,
P
<0.001).

Conclusions

Cardiac rehabilitation protects against the expansion of small
AAA
s and mitigates the risk associated with
AAA
repair, possibly because of the decreased elevation of blood pressure during exercise.

Clinical Trial Registration

URL:
upload.umin.ac.jp
. Unique identifier:
UMIN
000028237.
Geographic Modeling to Quantify the Impact of Primary and Comprehensive Stroke Center Destination Policies
Authors: Mullen Michael T. , Pajerowski William , Messé Steven R. , Mechem C. Crawford , Jia Judy , Abboud Michael , David Guy , Carr Brendan G. , Band Roger 
Published: February 2018

Background and Purpose—
We evaluated the impact of a primary stroke center (PSC) destination policy in a major metropolitan city and used geographic modeling to evaluate expected changes for a comprehensive stroke center policy.

Methods—
We identified suspected stroke emergency medical services encounters from 1/1/2004 to 12/31/2013 in Philadelphia, PA. Transport times were compared before and after initiation of a PSC destination policy on 10/3/2011. Geographic modeling estimated the impact of bypassing the closest hospital for the closest PSC and for the closest comprehensive stroke center.

Results—
There were 2 326 943 emergency medical services runs during the study period, of which 15 099 had a provider diagnosis of stroke. Bypassing the closest hospital for a PSC was common before the official policy and increased steadily over time. Geographic modeling suggested that bypassing the closest hospital in favor of the closest PSC adds a median of 3.1 minutes to transport time. Bypassing to the closest comprehensive stroke center would add a median of 8.3 minutes.

Conclusions—
Within a large metropolitan area, the time cost of routing patients preferentially to PSCs and comprehensive stroke centers is low.
Facial Palsy Following Embolization of a Juvenile Nasopharyngeal Angiofibroma
Authors: Tawfik Kareem O. , Harmon Jeffrey J. , Walters Zoe , Samy Ravi , de Alarcon Alessandro , Stevens Shawn M. , Abruzzo Todd 
Published: February 2018

Objectives: To describe a case of the rare complication of facial palsy following preoperative embolization of a juvenile nasopharyngeal angiofibroma (JNA). To illustrate the vascular supply to the facial nerve and as a result, highlight the etiology of the facial nerve palsy. Methods: The angiography and magnetic resonance (MR) imaging of a case of facial palsy following preoperative embolization of a JNA is reviewed. Results: A 13-year-old male developed left-sided facial palsy following preoperative embolization of a left-sided JNA. Evaluation of MR imaging studies and retrospective review of the angiographic data suggested errant embolization of particles into the petrosquamosal branch of the middle meningeal artery (MMA), a branch of the internal maxillary artery (IMA), through collateral vasculature. The petrosquamosal branch of the MMA is the predominant blood supply to the facial nerve in the facial canal. The facial palsy resolved since complete infarction of the nerve was likely prevented by collateral blood supply from the stylomastoid artery. Conclusions: Facial palsy is a potential complication of embolization of the IMA, a branch of the external carotid artery (ECA). This is secondary to ischemia of the facial nerve due to embolization of its vascular supply. Clinicians should be aware of this potential complication and counsel patients accordingly prior to embolization for JNA.
More action needed: Psychotropic prescribing in Australian residential aged care
Authors: Westbury Juanita , Gee Peter , Ling Tristan , Kitsos Alex , Peterson Gregory 
Published: February 2018

Objective: For at least two decades, concerns have been raised about inappropriate psychotropic prescribing in Australian residential aged care facilities, due to their modest therapeutic benefit and increased risk of falls and mortality. To date, the majority of prevalence data has been collected in Sydney exclusively and it is not known if recent initiatives to promote appropriate psychotropic prescribing have impacted utilisation. Thus, we aimed to comprehensively analyse psychotropic use in a large national sample of residential aged care facility residents. Method: A cross-sectional, retrospective cohort study of residents from 150 residential aged care facilities distributed nationally during April 2014–October 2015. Antipsychotic, anxiolytic/hypnotic and antidepressant utilisation was assessed, along with anticonvulsant and anti-dementia drug use. Negative binomial regression analysis was used to examine variation in psychotropic use. Results: Full psychotropic prescribing data was available from 11,368 residents. Nearly two-thirds (61%) were taking psychotropic agents regularly, with over 41% prescribed antidepressants, 22% antipsychotics and 22% of residents taking benzodiazepines. Over 30% and 11% were charted for ‘prn’ (as required) benzodiazepines and antipsychotics, respectively. More than 16% of the residents were taking sedating antidepressants, predominantly mirtazapine. South Australian residents were more likely to be taking benzodiazepines ( p < 0.05) and residents from New South Wales/Australian Capital Territory less likely to be taking them ( p < 0.01), after adjustment for rurality and size of residential aged care facility. Residents located in New South Wales/Australian Capital Territory were also significantly less likely to take antidepressants ( p < 0.01), as were residents from outer regional residential aged care facilities ( p < 0.01). Antipsychotic use was not associated with State, rurality or residential aged care facility size. Conclusion: Regular antipsychotic use appears to have decreased in residential aged care facilities but benzodiazepine prevalence is higher, particularly in South Australian residential aged care facilities. Sedating antidepressant and ‘prn’ psychotropic prescribing is widespread. Effective interventions to reduce the continued reliance on psychotropic management, in conjunction with active promotion of non-pharmacological strategies, are urgently required.
Ménière's Disease
Authors: Morrison Andrew W 
Published: February 2018

The otological practice at The London Hospital provides very large numbers of patients with Ménière's disease from a busy department. This clinical material has been utilized as much as possible, without research assistants or funds, to examine some clinical and pathological aspects of the disease which might have a bearing on aetiology. The investigation procedures which are likely to lead to an earlier and more certain diagnosis are outlined and prognostic indicators are mentioned. It would appear that there may be an hereditary predisposition to progressive idiopathic endolymphatic hydrops. Potential sufferers tend to have migraine, a family history of migraine, minor degrees of basilar impression associated with an abnormally located endolymphatic duct and sac, a more emotional personality, and possibly an association with blood group A. The experimental and clinicopathological evidence supports the view that the endolymphatic duct and sac have an important role in the pathogenesis of both idiopathic and secondary hydrops. Ultrastructural examination is continuing and may shed more light on the pathology at a cellular level. There is, as yet, no cure for Ménière's disease and sufferers will be incapacitated in varying degrees, often severely, for the rest of their days.
Oxygen Tension Measurement Using an Automatic Blood Gas Analyser
Authors: Becket J , Chakrabarti M K , Gillies I D S , Orchard C , Hall G M , Bourdillon P J 
Published: February 2018

Two different methods of assessing the reliability of the oxygen electrode of one model of an automatic blood gas analyser (BGA) have been studied. In the first, a single automatic BGA was assessed by using outdated bank blood which was pumped around a small extracorporeal circuit into which known gas mixtures were passed. Oxygen tension was varied between 2 and 16 kPa. In the second, fresh heparinized blood was tonometered with calibrated gases and submitted to the automatic BGA used in the first part of the study and also to three other identical machines. Each of the machines was between 3 and 4 years old. Eighteen different units of blood were used in the first part of the study. The correlation coefficient between the automatic BGA and the Po2 in the extracorporeal circuit varied between 0.29 and 0.99. 31% of the total of 209 measurements made by the automatic BGA were more than 1.2 kPa from the reference value, 25% of them being between 1.2 and 4.0 kPa from the reference value. In the second part of the study, the correlation coefficient between this automatic BGA and the tonometered blood was 0.96. The correlation coefficients for the 3 other identical BGAs were 0.84, 0.97 and 0.88, indicating that the BGA used in the first part of the study was no worse than any of the others. It is suggested that although clinicians are likely to ignore readings of an automatic BGA that are more than 4.0 kPa from the true value and are likely to repeat the investigation, readings between 1.2 and 4.0 kPa from the true value may adversely affect patient management.
Relationship between Protein Binding and Extravascular drug Concentrations of a Water-soluble Drug, Cytosine Arabinoside
Authors: Johnston A , Piall E M , Turner P , Slevin M L , Woollard R C , Lister T A 
Published: February 2018

The degree of binding of a drug to plasma proteins has a marked effect on its distribution, elimination, and pharmacological effect. Since only the unbound fraction is available for distribution into extravascular space, the ratio of drug in cerebrospinal fluid (CSF) or saliva to that in plasma is often regarded as a physiological measure of the free fraction of a drug. CSF: plasma and saliva: plasma ratios of cytosine arabinoside (araC) have been measured in patients with acute leukaemia and found to be 0.1–0.28, implying a binding of 72–90%. The protein binding of araC was measured by equilibrium dialysis in the plasma of patients with acute leukaemia at presentation. The mean binding ratio was 2.3 ± 6.8, implying that there was little or no protein binding. There was no correlation between alpha — 1 acid glycoprotein (AAG) levels and protein binding. The low CSF and saliva: plasma araC ratios found, suggest that drugs such as araC which have low lipid solubility do not pass freely into extravascular space. Thus the CSF or saliva: plasma ratio cannot be considered a good physiological measure of protein binding for drugs with poor lipid solubility.
Early Diagnosis and Surgical Management of Acoustic Neuroma: Is it Cost Effective?
Authors: Moffat D A , Hardy D G 
Published: February 2018

Audiological and radiological advances and refinement of microsurgical techniques have facilitated the diagnosis and excision of very small acoustic nerve tumours with a low morbidity and mortality. Is this cost effective? In an attempt to answer this question, an analysis of 66 cases of surgically treated acoustic neuromas is presented. This represents a part of a series of otoneurosurgical procedures carried out at Addenbrooke's Hospital over the last five years. By studying the relative morbidity of early and late surgical intervention in these cases, and by costing the exercise, the justification for early diagnosis and treatment is presented both in financial and human terms.
Blood Ordering Habits for Elective Surgery: Time for Change
Authors: Juma T , Baraka A , Abu-Lisan M , Asfar S K 
Published: February 2018

A prospective study was carried out for 6 months to determine the efficacy of blood ordering routines for elective surgery. It was found that only 23% of procedures needed preoperative crossmatching of blood (transfusion index ‘IT’ >0.5). There was an excessive over-ordering of blood for 77% of the operations (crossmatch/transfusion ratio >2.5). In addition, the transfusion index for the latter group showed that there was no need to prepare blood preoperatively (TI <0.5). A transfusion tariff is worked out which abandons crossmatching for the majority of procedures (cholecystectomy, thyroidectomy and surgery for duodenal ulcer excluding gastrectomy). Instead a ‘group and screen’ policy is suggested.