bluuebunny/crossref_metadata_2025 huggingface dataset:
American Urogynecologic Society Consensus Statement: Cystoscopy at the Time of Prolapse Repair
Authors: Cohen Seth A. , Carberry Cassandra L. , Smilen Scott W.
Published: January 2018

Injury to the urinary tract is a known risk of surgical repair of anterior and apical pelvic organ prolapse. Cystoscopy at the time of surgical prolapse repair is a low-risk procedure that can identify genitourinary tract injury by inspecting the bladder and urethra as well as by visualizing the ureters and ureteral efflux. There are several techniques to assist with visualization of ureteral efflux. Identifying injury intraoperatively may allow for mitigation of the morbidity of the injury. Universal cystoscopy should be performed at the time of all pelvic reconstructive surgeries, with the exception of operations solely for posterior compartment defects.
Abdominal Sacrocolpopexy for Repair of Pelvic Organ Prolapse After Radical Cystectomy
Authors: Zimmern Philippe E. , Wang Connie N.
Published: January 2018

Introduction

Most case series describing surgical repair for pelvic organ prolapse (POP) after radical cystectomy (RC) focus on transvaginal repairs. We present our experience of POP after RC repaired by abdominal mesh sacrocolpopexy (ASC) with long-term follow-up.

Methods

Two women with previous RC with ileal conduit diversion underwent open ASC for repair of apical prolapse with concomitant enterocele. Prolapse severity was assessed using the POP quantification staging system, whereas pelvic imaging was performed with magnetic resonance imaging defecography.

Results

One patient had no POP recurrence at follow-up of 45 months after ASC. The other patient had anterior enterocele recurrence at 11 months after ASC and was treated with a limited outpatient transvaginal repair. She had no POP recurrence at 12 months after secondary repair. Both ASC procedures had technical challenges related to pelvic dissection of adhesed loops of bowels, access to the promontory, and retroperitonealization requiring the assistance of a general surgeon. Neither case had perioperative complications.

Conclusion

In women with large enterocele or vaginal vault prolapse after RC, repair with ASC, although technically challenging, can offer durable POP outcomes.
Effect of door-to-angioembolization time on mortality in pelvic fracture: Every hour of delay counts
Authors: Matsushima Kazuhide , Piccinini Alice , Schellenberg Morgan , Cheng Vincent , Heindel Patrick , Strumwasser Aaron , Benjamin Elizabeth , Inaba Kenji , Demetriades Demetrios
Published: January 2018

INTRODUCTION

Angioembolization (AE) is widely used for hemorrhagic control in patients with pelvic fracture. The latest version of the Resources for Optimal Care of the Injured Patient issued by the American College of Surgeons Committee on Trauma requires interventional radiologists to be available within 30 minutes to perform an emergency AE. However, the impact of time-to-AE on patient outcomes remains unknown. We hypothesized that a longer time-to-AE would be significantly associated with increased mortality in patients with pelvic fracture.

METHODS

This is a 2-year retrospective cohort study using the American College of Surgeons Trauma Quality Improvement Program database from January 2013 to December 2014. We included adult patients (age ≥ 18 years) with blunt pelvic fracture who underwent pelvic AE within 4 hours of hospital admission. Patients who required any hemorrhage control surgery for associated injuries within 4 hours were excluded. Hierarchical logistic regression was performed to evaluate the impact of time-to-AE on in-hospital and 24-hour mortality.

RESULTS

A total of 181 patients were included for analysis. The median age was 54 years (interquartile range, 38–68) and 69.6% were male. The median injury severity score was 34 (interquartile range, 27–43). Overall in-hospital mortality rate was 21.0%. The median packed red blood cell transfusions within 4 and 24 hours after admission were 4 and 6 units, respectively. After adjusting for other covariates in a hierarchical logistic regression model, a longer time-to-pelvic AE was significantly associated with increased in-hospital mortality (odds ratio, 1.79 for each hour; 95% confidence interval, 1.11–2.91; p = 0.018).

CONCLUSION

The current study showed an increased risk of in-hospital mortality related to a prolonged time-to-AE for hemorrhagic control following pelvic fractures. Our results suggest that all trauma centers should allocate resources to minimize delays in performing pelvic AE.

LEVEL OF EVIDENCE

Therapeutic/care management, level IV.
Abdominal trauma surgery during recent US combat operations from 2002 to 2016
Authors: Stockinger Zsolt T. , Turner Caryn A. , Gurney Jennifer M.
Published: January 2018

BACKGROUND

Abdominal surgery constitutes approximately 13% of surgical procedures performed for combat injuries. This study examines the frequencies and type of abdominal surgical procedures performed during recent US Military operations.

METHODS

A retrospective analysis of the Department of Defense Trauma Registry was performed for all Role 2 (R2) and Role 3 (R3) medical treatment facilities (MTFs), from January 2002 to May 2016. The 273 International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes that were identified as abdominal surgical procedures were stratified into 24 groups based on anatomic and functional classifications and then grouped by whether they were laparoscopic. Procedure grouping and categorization were determined, and adjudicated if necessary, by subject matter experts. Data analysis used Stata version 14 (College Station, TX).

RESULTS

A total of 26,548 abdominal surgical procedures were identified at R2 and R3 MTFs. The majority of abdominal surgical procedures were reported at R3 facilities. The largest procedure group at both R2 and R3 MTFs were procedures involving the bowel. There were 18 laparoscopic procedures reported (R2: 4 procedures, R3: 14 procedures). Laparotomy not otherwise specified was the second largest procedure group at both R2 (1,060 [24.55%]) and R3 (4,935 [22.2%]) MTFs. Abdominal caseload was variable over the 15-year study period.

CONCLUSIONS

Surgical skills such as open laparotomy and procedures involving the bowel are crucial in war surgery. The abundance of laparotomy not otherwise specified may reflect inadequate documentation, or the plethora of second- and third-look operations and washouts performed for complex abdominal injuries. Traditional elective general surgical cases (gallbladder, hernia) were relatively infrequent. Laparoscopy was almost nonexistent. Open abdominal surgical skills therefore remain a necessity for the deployed US Military General Surgeons; this is at odds with the shifting paradigm from open to laparoscopic skills in stateside civilian and military hospitals.

LEVEL OF EVIDENCE

Epidemiologic study, level III.
Functional stability of the TEG 6s hemostasis analyzer under stress
Authors: Meledeo Michael Adam , Peltier Grantham C. , McIntosh Colby S. , Voelker Chet R. , Bynum James A. , Cap Andrew P.
Published: January 2018

BACKGROUND

Viscoelastic measurements of coagulation provide much needed information, including guidance for triage and insight into bleeding disorders. The current clinical standards for these devices are the thromboelastogram (TEG) 5000 and the rotational thromboelastometer (ROTEM) delta, but a new product, the TEG 6s, has recently come to market, designed to simplify the user experience, reduce the required blood volume, and conduct multiple assays simultaneously. This study compares the performance of these three devices and examines the resiliency of the TEG 6s under various stresses.

METHODS

The variances of coagulation metrics obtained by the TEG 6s (prototype and production models), TEG 5000, and ROTEM delta were compared using manufacturers' reagents and citrate-collected blood from healthy donors. Variability between devices was examined, and their performances under various motion and temperature stresses were compared by placing one unit on a linear or orbital shaker, in the cold, or in the heat while a counterpart remained stationary at room temperature.

RESULTS

Although most comparable parameters had low degrees of variance, there were small but significantly increased variances found in some ROTEM delta and TEG 5000 parameters versus comparable TEG 6s parameters. Orbital rotation of the TEG 6s had no effect on means of any parameter but resulted in increased variance of 2 parameters, but linear motion with sudden striking had no observed impact on results. Similarly, 7-day exposure to heat (45°C) or cold (4°C) only resulted in minor deviations within normal ranges of the TEG 6s.

DISCUSSION

The TEG 6s provides several improvements over other coagulation analyzers: it is easier to use and robustly resilient against motion and temperature stresses. These features suggest that it may be capable of deployment not only in the clinical laboratory but also to a variety of austere settings.

LEVEL OF EVIDENCE

Diagnostic test, level III.
A review of the landscape: Challenges and gaps in trauma response to civilian high threat mass casualty incidents
Authors: Callaway David W.
Published: January 2018

The ultimate goal of the emergency response and trauma system is to reduce potentially preventable death from trauma. Tremendous advances in trauma care emerged from the past 15 years of United States’ combat engagements around the globe. Unfortunately, combat and insurgency tactics have also metastasized to the civilian world, resulting in increasingly complex and dynamic acts of intentional mass violence. These high threat active violent incidents (AVIs) pose significant preparedness, response, and clinical care challenges to the civilian healthcare systems. Currently, there are several operational and policy gaps that limit the successful preparedness and response to AVIs and dynamic MCIs in the United States.
Comparison of Foot Pressure and Center of Force During Sit-to-Stand and Stand-to-Sit Movements in Older Adults With Good and Poor Visual Acuity
Authors: Shin Sun-Shil , An Duk-Hyun , Yoo Won-Gyu
Published: January 2018

We investigated the influence of visual acuity on foot pressure (FP) and center of force (COF) during sit-to-stand (SitTS) and stand-to-sit (STSit) movements in older adults. We recruited 20 older adult subjects, 10 with binocular visual acuity (BVA) of 0.4 log minimum angle of resolution (logMAR) or more (poor BVA group) and 10 with BVA of 0.3 logMAR or less (good BVA group), from the local community. Both FP and COF were measured using the CONFORMat System while the subjects performed SitTS and STSit movements. The values of FP and COF were significantly lower during both tasks in the good BVA group than in the poor BVA group. Our results suggest that older adults with poor vision were more balance challenged than older adults with good BVA. In addition, they need to rely more on a novel strategy such as armrests to reduce the COF trajectory and to make sure about stability during the SitTS and STSit movements.
Cognitive Aging and Changes in Brain Morphology
Authors: Carroll Melissa A.
Published: January 2018

Cognitive aging can produce morphological brain changes that contribute to cognitive impairments different from the neuropathological presentation of disease. To understand age-related changes to human cognition, it is important to recognize normal morphological changes that occur within the aging brain. The purpose of this narrative review is to familiarize the reader with current concepts in neurocognitive aging, summarize current evidence regarding structural and functional connectivity changes, and briefly discuss a relationship between the aging brain, morphological changes, and cerebral hemodynamics.
The Evolving Interconnectedness of 3 Fields of Study
Authors: McCarthy Lise Ellen
Published: January 2018

For almost 40 years, falls research has progressed without a consensus on a universal definition of how falls are defined. This lack of consensus affects the scope and validity of falls research and fall prevention and early detection programs. A universal definition should include meaningful language that is relatable to multiple stakeholders (eg, people who fall, clinical experts on falls). Broad consideration of what a fall is and how to treat a fall may help improve consensus and improve clinical treatment approaches to reduce fall risk. This article highlights research on falls, brain imaging, and cognitive therapy that supports links between falls, white matter changes in the brain, cognition, and physical activity. The studies presented focus on dementia and Parkinson disease because these populations have profound neurodegenerative white matter changes and the highest rates of falling.
Dual-Task Rehabilitation
Authors: Studer Mike
Published: January 2018

Evidence has consistently established that older people with a higher frequency of falls are more likely to be affected by environmental stimuli or simultaneous responsibilities while attempting to maintain balance. Physical therapists have the skill and technology to evaluate a patient's ability to combine tasks and to measure their tolerance of distractions. The science of dual-task testing, documentation, and rehabilitation has provided insight into who can be helped, how to help them, and how to aid in compensation when rehabilitation has not succeeded. This article reviews all of the aforementioned aspects of dual task for older patients, and some diagnostic groups, including some insight to the neurophysiology as well.
Improved Cuff Technique and Intraoperative Detection of Vascular Complications for Hind Limb Transplantation in Mice
Authors: Kim Minhyung , Fisher Daniel T. , Powers Colin A. , Repasky Elizabeth A. , Skitzki Joseph J.
Published: January 2018

Background

Vascularized composite tissue allotransplantation (VCA) from a cadaveric donor has now become a clinical reality and the treatment modality of choice for patients with devastating injuries, deformities, and complex tissue defects. However, many VCA patients experience severe toxicities due to the strong immunosuppression required secondary to high antigenicity of the grafts. To improve immunosuppressive protocols for VCA, feasible and reliable preclinical models are necessary. The purpose of this study was to introduce new techniques to an established preclinical VCA model to accelerate future investigations.

Methods

C57BL/6 (H-2b) and BALB/c (H-2d) mice were used to perform VCA as recipients and donors, respectively. Surgery time, success rate, associated complications, and mortality were analyzed. Blood flow in grafts was interrogated with laser speckle image (LSI).

Results

A nonsuture cuff technique was used with the abdominal aorta for end-to-end anastomosis. The cuff technique demonstrated efficiency for donor surgery (52 ± 10 minutes for donor vs. 45 ± 8 minutes for recipient surgery). Successful revascularization was achieved in 27 (90%) of 30 transplants. The majority of surgical complications occurred within 48 hours including artery occlusion, venous occlusion, cerebral stroke, and minor bleeding without mortality. LSI was useful in detecting intraoperative vascular complications with display patterns predictive of complication type.

Conclusions

The described techniques may facilitate a more efficient heterotopic hind limb transplantation mouse model of VCA.
Risk of Acute Ischemic Stroke in Patients With Monocular Vision Loss of Vascular Etiology
Authors: Zhang Lucy Y. , Zhang Jason , Kim Richard K. , Matthews Jared L. , Rudich Danielle S. , Greer David M. , Lesser Robert L. , Amin Hardik
Published: January 2018

Background:

To evaluate the risk of concurrent acute ischemic stroke and monocular vision loss (MVL) of vascular etiology.

Design:

Retrospective, cross-sectional study.

Subjects:

Patients aged 18 or older diagnosed with MVL of suspected or confirmed vascular etiology who had no other neurologic deficits and who received brain MRI within 7 days of onset of visual symptoms were included.

Methods:

A medical record review was performed from 2013 to 2016 at Yale New Haven Hospital. Patients were included if vision loss was unilateral and due to transient monocular vision loss (TMVL), central retinal artery occlusion (CRAO), or branch retinal artery occlusion (BRAO). Any patients with neurologic deficits other than vision loss were excluded. Other exclusion criteria were positive visual phenomena, nonvascular intraocular pathology, and intracranial pathology other than ischemic stroke.

Main Outcome Measures:

The presence or absence of acute stroke on diffusion-weighted imaging (DWI) on brain MRI.

Results:

A total of 641 records were reviewed, with 293 patients found to have MVL. After excluding those with focal neurologic deficits, there were 41 patients who met the inclusion criteria and received a brain MRI. Eight of the 41 subjects (19.5%) were found to have findings on brain MRI positive for acute cortical strokes. The proportion of lesion positive MRI was 1/23 (4.3%) in TMVL subjects, 4/12 (33.3%) in CRAO subjects, and 2/5 (40%) in BRAO subjects. Brain computed tomography (CT) scans were not able to identify the majority of acute stroke lesions in this study.

Conclusions:

Patients with MVL of vascular etiology such as TMVL, CRAO, or BRAO may have up to 19.5% risk of concurrent ischemic stroke, even when there are no other neurologic deficits. These strokes were detected acutely with brain MRI using DWI but were missed on CT.
Reference-dependent preferences arise from structure learning
Authors: Hunter Lindsay E. , Gershman Samuel J.
Published: January 2018

Modern theories of decision making emphasize the reference-dependency of decision making under risk. In particular, people tend to be risk-averse for outcomes greater than their reference point, and risk-seeking for outcomes less than their reference point. A key question is where reference points come from. A common assumption is that reference points correspond to expectations about outcomes, but it is unclear whether people rely on a single global expectation, or multiple local expectations. If the latter, how do people determine which expectation to apply in a particular situation? We argue that people discover reference points using a form of Bayesian structure learning, which partitions outcomes into distinct contexts, each with its own reference point corresponding to the expected outcome in that context. Consistent with this theory, we show experimentally that dramatic change in the distribution of outcomes can induce the discovery of a new reference point, with systematic effects on risk preferences. By contrast, when changes are gradual, a single reference point is continuously updated.
Task-Evoked Functional Connectivity Does Not Explain Functional Connectivity Differences Between Rest and Task Conditions
Authors: Lynch Lauren K. , Lu Kun-Han , Wen Haiguang , Zhang Yizhen , Saykin Andrew J. , Liu Zhongming
Published: January 2018

During complex tasks, patterns of functional connectivity (FC) differ from those in the resting state. What accounts for such differences remains unclear. Brain activity during a task reflects an unknown mixture of spontaneous activity and task-evoked responses. The difference in FC between a task state and resting state may reflect not only task-evoked connectivity, but also changes in spontaneously emerging networks. Here, we characterized the difference in apparent functional connectivity between the resting state and when human subjects were watching a naturalistic movie. Such differences were marginally (3-15%) explained by the task-evoked networks directly involved in processing the movie content, but mostly attributable to changes in spontaneous networks driven by ongoing activity during the task. The execution of the task reduced the correlations in ongoing activity among different cortical networks, especially between the visual and non-visual sensory cortices. Our results suggest that the interaction between spontaneous and task-evoked activities is not mutually independent or linearly additive, and that engaging in a task may suppress ongoing activity.
Highly efficient chondrogenic differentiation of human iPSCs and purification via a reporter allele generated by CRISPR-Cas9 genome editing
Authors: Adkar Shaunak S. , Wu Chia-Lung , Willard Vincent P. , Dicks Amanda , Ettyreddy Adarsh , Steward Nancy , Bhutani Nidhi , Gersbach Charles A. , Guilak Farshid
Published: January 2018

The differentiation of human induced pluripotent stem cells (hiPSCs) to prescribed cell fates enables the engineering of patient-specific tissue types, such as hyaline cartilage, for applications in regenerative medicine, disease modeling, and drug screening. In many cases, however, these differentiation approaches are poorly controlled and generate heterogeneous cell populations. Here we demonstrate robust cartilaginous matrix production in three unique hiPSC lines using a highly efficient and reproducible differentiation protocol. To purify chondroprogenitors produced by this protocol, we engineered a COL2A1-GFP knock-in reporter hiPSC line by CRISPR-Cas9 genome editing. Purified chondroprogenitors demonstrated an improved chondrogenic capacity compared to unselected populations. The ability to enrich for chrondroprogenitors and generate homogenous matrix without contaminating cell types will be essential for regenerative and disease modeling applications.
Electron Paramagnetic Resonance Investigation of Nitrite Binding in Myoglobin
Authors: Bawn Matthew , MacMillan Fraser
Published: January 2018

It has been proposed that myoglobin (Mb) may act as a nitrite reductase under hypoxic conditions. Any mechanism describing such activity should take into account the binding geometry of the ligand to the heme. Crystal structures of horse-heart Mb and human hemoglobin-nitrite complexes suggest that the anion adopts an uncommonO-nitrito binding mode. Electron Paramagnetic Resonance (EPR) spectroscopy was employed to investigate the nature of nitrite binding to Mb at pH values ranging from 6.5 to 10.8. Results suggest that for ferric Mb at low pH, nitrite binds in theO-bound nitrito mode resulting in a low-spin (LS) iron center. Further a high-spin (HS) iron center is observed at high pH in Mb-Nitrite with spectral values different to that of purely HS-Mb that is proposed to be due to anN-bound nitrite. The yields of these two species were found to be influenced by pH.

Background

Myoglobin has been theorized to have a role as a nitrite reductase.

Results

O-bound nitrite produces a low-spin ferric heme complex, whilst at high pH a high-spin species is found proposed to be theN-bound form.

Conclusion

Nitrite may bind to heme in myoglobin via N-nitro or O-nitrito mode.

Significance

The mechanism of any nitrite reduction will depend on its binding to the heme cofactor.
Cooperative Cobinding of Synthetic and Natural Ligands to the Nuclear Receptor PPARγ
Authors: Shang Jinsai , Brust Richard , Mosure Sarah A. , Bass Jared , Munoz-Tello Paola , Lin Hua , Hughes Travis S. , Tang Miru , Ge Qingfeng , Kamenecka Theodore M. , Kojetin Douglas J.
Published: January 2018

Crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) have revealed overlapping binding modes for synthetic and natural/endogenous ligands, indicating competition for the orthosteric pocket. Here we show that cobinding of a synthetic ligand to the orthosteric pocket can push natural and endogenous PPARγ ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega (Ω) loop. X-ray crystallography, NMR spectroscopy, all-atom molecular dynamics simulations, and mutagenesis coupled to quantitative functional assays reveal that synthetic ligand and fatty acid cobinding can form a “ligand link” to the Ω loop and synergistically affect the structure and function of PPARγ. These findings contribute to a growing body of evidence indicating ligand binding to nuclear receptors can be more complex than the classical one-for-one orthosteric exchange of a natural or endogenous ligand with a synthetic ligand.
Species richness, habitat association and odonata diversity of the south-western region of Bangladesh
Authors: Tuhin Sajjad Hossain , Khan Md Kawsar
Published: January 2018

Odonata survey was conducted throughout the south-western region of Bangladesh, concentrated on eight districts and the Sundarban (the largest mangrove forest of the world) from August 2014 to August 2016. A total of 50 species under 30 genera belonging to six families were recorded during the study period. Among the 50 species, 31 species belong to Anisoptera whereas 19 species were recorded from the Zygoptera suborder. Libellulidae and Coenagrionidae were most dominant Anisoptetran and Zygopteran families with 28 and 17 species respectively. One Zygoptera speciesMortonagrion varalliwas newly added to the Odonata fauna of Bangladesh. Among surveyed habitats, species richness was highest in marshland with 38 species followed by 34 species in the lakeside. On the other hand, odonata diversity was lowest in the mangrove area. Our study shows a positive correlation between environmental variables (such as average rainfall, relative humidity, and average temperature) and species richness in the study area. Species richness is highest during monsoon and lowest in winter.
SlARF10, an auxin response factor, is required for chlorophyll and sugar accumulation during tomato fruit development
Authors: Mei Lihua , Yuan Yujin , Wu Mengbo , Gong Zehao , Zhang Qian , Yang Fengqing , Zhang Qiang , Luo Yingqing , Xu Xin , Zhang Wenfa , Miao Mingjun , Li Zhengguo , Deng Wei
Published: January 2018

Tomato green fruits photosynthesis contributes to fruit growth and carbon economy. Tomato auxin response factor 10 (SlARF10) is one of the members of ARF family. Our results showed that SlARF10 locates in the nucleus and has no transcriptional activity. SlARF10 was expressed in various tomato tissues, but highly expressed in green fruit. Up-regulation of SlARF10 produced dark green phenotype of fruits, whereas down-regulation of SlARF10 had light green phenotype. Autofluorescence and chlorophyll content analysis confirmed the phenotypes, which indicated that SlARF10 plays an important role in chlorophyll accumulation in tomato fruits. Up-regulation of SlARF10 increased the photochemical potential in tomato leaves and fruits. Furthermore, the SlARF10 up-regulating lines displayed improved accumulation of starch in fruits, whereas SlARF10 suppressed lines had inhibited starch accumulation. Up-regulation of SlARF10 increased the expression of AGPases, the starch biosynthesis genes. SlARF10 up-regulating lines had increased accumulation of SlGLK1 and SlGLK2 transcripts in fruits. The promoter sequence of SlGLK1 gene had two conserved ARF binding sites. SlARF10 may regulate the expression of SlGLK1, thus controlling chlorophyll accumulation, photosynthesis rates and sugars synthesis in fruits. Our study provided more insight on the link between auxin signaling, chloroplastic activity and sugar metabolism during the development of tomato fruits.

Abbreviations

ARFs

Auxin Response Factors

RNAi

RNA interference

GLK

GOLDEN2-LIKE

DET1/hp2

The DE-ETIOLATED 1

DDB1

UV-DAMAGED DNA-BINDING PROTEIN 1

KNOXs

Class I KNOTTED1-LIKE HOMEOBOX

GC-MS

Gas Chromatography-Mass Spectrometry

qRT-PCR

Quantitative real time PCR

TFs

Transcription factors

WT

Wild-type

MR

Middle region

DB domain

DNA binding domain

CTD

C-terminal interaction domain

AD

Transcriptional activators

RD

Transcriptional repressors

B3

N-terminal DNA-binding domain

Highlight

SlARF10 played an important role in the chlorophyll accumulation and photosynthesis in tomato fruits. SlARF10 was involved in starch accumulation by controlling the expression of starch synthesis related enzyme genes. SlARF10 may regulate the expression of SlGLK1, thus controlling chlorophyll accumulation, photosynthesis rates and sugars synthesis in tomato fruits.
Loss of E-cadherin enhances IGF1-IGF1R pathway activation and sensitizes breast cancers to anti-IGF1R inhibitors
Authors: Nagle Alison M. , Levine Kevin M. , Tasdemir Nilgun , Scott Julie A. , Burlbaugh Kara , Kehm Justin , Katz Tiffany A. , Boone David N. , Jacobsen Britta M. , Atkinson Jennifer M. , Oesterreich Steffi , Lee Adrian V.
Published: January 2018

Purpose

Insulin-like growth factor I (IGF1) signaling regulates breast cancer initiation and progression and associated cancer phenotypes. We previously identified E-cadherin (CDH1) as a repressor of IGF1 signaling and in this study examined how loss of E-cadherin affects IGF1R signaling and response to anti-IGF1R therapies in breast cancer.

Experimental Design

Breast cancer cell lines were used to assess how altered E-cadherin levels regulate IGF1R signaling and response to two anti-IGF1R therapies. In situ proximity ligation assay (PLA) was used to define interaction between IGF1R and E-cadherin. TCGA RNA-seq and RPPA data was used to compare IGF1R activation in estrogen receptor positive (ER+) invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) tumors. ER+ ILC cell lines and xenograft tumor explant cultures were used to evaluate efficacy to IGF1R pathway inhibition in combination with endocrine therapy.

Results

Diminished functional E-cadherin increased both activation of IGF1R signaling and efficacy to anti-IGF1R therapies. PLA demonstrated a direct endogenous interaction between IGF1R and E-cadherin at points of cell-cell contact. Increased expression of IGF1 ligand and levels of IGF1R phosphorylation were observed in E-cadherin deficient ER+ ILC compared to IDC tumors. IGF1R pathway inhibitors were effective in inhibiting growth in ER+ ILC cell lines and synergized with endocrine therapy and similarly IGF1R inhibition reduced proliferation in ILC tumor explant culture.

Conclusions

We provide evidence that loss of E-cadherin hyperactivates the IGF1R pathway and increases sensitivity to IGF1R targeted therapy, thus identifying the IGF1R pathway as a potential novel target in E-cadherin deficient breast cancers.

STATEMENT OF SIGNIFICANCE

IGF1R signaling is an attractive therapeutic target in breast cancer due to its regulation of proliferation, migration, and invasion. However, clinical trials targeting IGF1R have largely been unsuccessful due to lack of biomarkers to stratify patients for therapeutic response. In this study, we demonstrate loss of E-cadherin as a potential biomarker for response to anti-IGF1R therapy, and show efficacy of IGF1R inhibition in ER+ ILC in combination with endocrine therapy. Patients with ER+ ILC have poorer long-term outcomes than patients with ER+ IDC and have a propensity for increased late recurrences, highlighting the need for improved therapeutic strategies for this subtype of breast cancer. Here, we credential IGF1R inhibition as a novel therapeutic strategy in combination with endocrine therapy for the treatment of ER+ ILC.
Gene Expression-Based Drug Repurposing to Target Ageing
Authors: Dönertaş Handan Melike , Valenzuela Matías Fuentealba , Partridge Linda , Thornton Janet M.
Published: January 2018

Ageing is the largest risk factor for a variety of non-communicable diseases. Model organism studies have shown that genetic and chemical perturbations can extend both life- and health-span. Ageing is a complex process, with parallel and interacting mechanisms contributing to its aetiology, posing a challenge for the discovery of new pharmacological candidates to ameliorate its effects. In this study, instead of a target-centric approach, we adopt a systems level drug repurposing methodology to discover drugs that could combat ageing in human brain. Using multiple gene expression datasets from brain tissue, taken from patients of different ages, we first identified the expression changes that characterise ageing. Then, we compared these changes in gene expression with drug perturbed expression profiles in the Connectivity Map. We thus identified 24 drugs with significantly associated changes. Some of these drugs may function as anti-ageing drugs by reversing the detrimental changes that occur during ageing, others by mimicking the cellular defense mechanisms. The drugs that we identified included significant number of already identified pro-longevity drugs, indicating that the method can discover de novo drugs that meliorate ageing. The approach has the advantages that, by using data from human brain ageing data it focuses on processes relevant in human ageing and that it is unbiased, making it possible to discover new targets for ageing studies.
Role of IQGAP1 in Head and Neck Carcinogenesis
Authors: Wei Tao , Choi Suyong , Buehler Darya , Rapraeger Alan C. , Anderson Richard A. , Lambert Paul F.
Published: January 2018

Head and neck squamous cell carcinoma (HNSCC) is a common cancer in humans. Phosphoinositide 3-kinase (PI3K)/AKT signaling, along with its downstream effector mTOR, is one of the most frequently altered pathways in HNSCC, and is downstream of growth factor signaling including that mediated by epidermal growth factor receptor (EGFR), which is also commonly upregulated in HNSCC. Recently, IQ motif-containing GTPase activation protein 1 (IQGAP1) has been reported to function as a scaffold for the enzymes involved in the PI3K/AKT signaling pathway. Iqgap1 gene expression is increased in human HNSCCs, raising the hypothesis that it acts as an oncogene in this cancer. Whether IQGAP1 is necessary for HNSCC development as well as what is its underlying mechanism are both unknown. Here we report on the role of IQGAP1 in HNSCC by performing a combination of in vitro studies using human cancer cell lines, and in vivo studies using a well-validated preclinical mouse model for HNSCC that is known to depend upon EGFR signaling. Cells knocked out for IQGAP1 lost AKT signaling. Disruption of IQGAP1-scaffolded PI3K/AKT signaling using a peptide that interferes with the ability of IQGAP1 to bind to PI3K reduced HNSCC cell survival. In vivo studies utilizing Iqgap1-null (Iqgap1-/-) mice demonstrated that IQGAP1 is necessary for efficient PI3K signaling upon EGF-stimulation. Treatment of Iqgap1-/- mice with the oral carcinogen, 4-nitroquinoline 1-oxide (4NQO), Iqgap1-/- led to significantly lower multiplicities of cancer foci as well as significantly lower numbers of high grade cancers than observed in similarly treated Iqgap1+/+ mice. IQGAP1 protein was increased in its expression in HNSCCs arising in the Iqgap1+/+ mice, consistent with that seen in human HNSCCs. We also observed a significant down-regulation of PI3K signaling in 4NQO-induced HNSCCs arising in the Iqgap1-/- mice, consistent with IQGAP1 contributing to carcinogenesis by promoting PI3K signaling. Our studies, therefore, support the hypothesis that IQGAP1 acts as an oncogene in head and neck carcinogenesis, and provide mechanistic insight into its role.
A new MR-SAD algorithm for the automatic building of protein models from low-resolution X-ray data and a poor starting model
Authors: Skubák Pavol , Araç Demet , Bowler Matthew W. , Correia Ana R. , Hoelz Andre , Larsen Sine , Leonard Gordon A. , McCarthy Andrew A. , McSweeney Sean , Mueller-Dieckmann Christoph , Otten Harm , Salzman Gabriel , Pannu Navraj S.
Published: January 2018

Determining macromolecular structures from X-ray data with resolution worse than 3 Å remains a challenge. Even if a related starting model is available, its incompleteness or its bias together with a low observation-to-parameter ratio can render the process unsuccessful or very time-consuming. Yet, many biologically important macromolecules, especially large macromolecular assemblies, membrane proteins and receptors, tend to provide crystals that diffract to low resolution. A new algorithm to tackle this problem is presented that uses a multivariate function to simultaneously exploit information from both an initial partial model and low-resolution single-wavelength anomalous diffraction data. The new approach has been used for six challenging structure determinations, including the crystal structures of membrane proteins and macromolecular complexes that have evaded experts using other methods, and large structures from a 3.0 Å resolution F1-ATPase data set and a 4.5 Å resolution SecYEG–SecA complex data set. All of the models were automatically built by the method toRfreevalues of between 28.9 and 39.9% and were free from the initial model bias.
Knowledge exchange and management research: barriers and potentials
Authors: Bager Torben
Published: January 2018

Purpose

The growing involvement of management researchers in knowledge exchange activities and collaborative research does not seem to be reflected in a growing academic output. The purpose of this paper is to explore barriers for the limited academic output from these activities as well as the potential for ‘interesting’ papers.

Design/methodology/approach

The paper uses secondary data and statistics as well as an illustrative case study to trace knowledge exchange activities and barriers for academic output based on these activities.

Findings

The paper identifies a number of barriers for the turning of data derived from knowledge exchange activities into academic papers such as low priority of case study research in leading management journals, a growing practice orientation in the research funding systems, methodological challenges because of limited researcher control and disincentives for researcher involvement in knowledge exchange activities. The paper also identifies a potential for ‘interesting’ research and discoveries through collaborative research.

Research limitations/implications

Diminishing the barriers for collaborative and case-based research and exploring the potential for ‘interesting’ discoveries has the potential to increase the number of published papers with a high level of scientific rigor as well as a high level of relevance for practice.

Originality/value

An outcome focus on the relationship between knowledge exchange activities and management research is to the author’s knowledge new in the debate about weak practical relevance of management research.
Bridging the relevance-ranking chasm: mission impossible?
Authors: Zolkiewski Judy
Published: January 2018

Purpose

This paper aims to debate the challenges related to balancing relevance and ranking in management research.

Design/methodology/approach

This is a commentary on and review of challenges faced by twenty-first century management academics.

Findings

There is a chasm between managerial relevance and current managerial research; however, with academic buy-in, there are ways in which the chasm can be crossed.

Research limitations/implications

The implications of this are wide reaching for management researchers. They are challenged to consider different methodologies, strategies and dissemination avenues for their research.

Practical implications

Researchers need to consider not only collaboration with practitioners, as they pursue solutions to managerial problems, but also more inter-disciplinary research that addresses the wicked problems of management in practice.

Social implications

Solving the challenge of managerial relevance of business research has the potential to allow the contribution of business academia to be fully appreciated by practitioners.

Originality/value

The value of this thought-piece is that it challenges business and management academics to challenge the status quo and fight to make their research relevant to and valued by the business world.
Questionable research practices in academia: antecedents and consequences
Authors: Grant David B. , Kovács Gyöngyi , Spens Karen
Published: January 2018

Purpose

The purpose of this paper is to discuss questionable research practices (QRPs) in business research, particularly in the logistics and supply chain management discipline, in light of antecedents influenced by the current academic environment and the consequences for academic rigour and relevance to stimulate thinking and debate among the academic community.

Design/methodology/approach

A literature review and autoethnographic approach were used to examine these issues based on over 60 years’ collective academic experience of the authors. Data were collected from discussions among the paper’s authors as well as recounting open discussions with other academics and journal editors to collate their observations.

Findings

Evidence is provided of issues the authors have seen first-hand where antecedents in the academic environment influences QRPs, which then detrimentally affect research rigour and relevance, integrity and proper contributions to ground-breaking research and knowledge advancement.

Research limitations/implications

This paper is based on personal observations and experiences of the three authors as well as open-ended discussions with others in the academic community. Suggestions are provided for various academic stakeholders to address these issues.

Practical implications

Practical implications are only provided for academics in their roles as authors, journal editors and reviewers.

Social implications

Encouraging the academic community to eliminate QRPs to improve the rigour, relevance and quality of research will provide more credibility and integrity resulting in better impact and outcomes for society at large.

Originality/value

The value of this paper is in stimulating thinking and debate among academics to return to core issues and values in academia opposed to focusing on narrow university goals focussed on other antecedents of QRPs.
Smart tourism destination triggers consumer experience: the case of Porto
Authors: Liberato Pedro , Alen Elisa , Liberato Dalia
Published: January 2018

Purpose

The purpose of this paper is to emphasize the increasing importance of information and communication technologies (ICTs) in smart tourism destinations, in their integration in the activity of the tourism companies, and in their interaction with visitors/tourists. In summary, it is intended to evaluate in the city of Porto how the use of technology before, during and after the visit influences the tourist experience.

Design/methodology/approach

The authors empirically investigate the importance of using ICTs during tourism experience, assess the access/availability of ICT at the destination and its importance in tourist’s decisions. It is analyzed if the applications and/or information available on the internet are important and positively influence the tourism experience in Porto, that is, the degree of tourist satisfaction. The empirical evidence is based on a quantitative analysis, using a data set involving 423 tourists in the city of Porto.

Findings

The importance of the internet access at the destination, especially in places like airports and hotels, since most tourists are primarily using their mobile devices and computers during the trip, and the existing information technologies available in the destination (internet, smartphones or other mobile devices and applications) are considered very important in explaining tourists’ experience.

Originality/value

This study identifies the strengths and weaknesses of the technological strategies, providing useful information for destination management, discussing innovation in tourism, and proposing a framework that empirically evaluates how technological components used in smart tourism destinations can improve tourists’ experiences.
Treatment of silence as misrepresentation in contracts
Authors: Karim Ridoan , Sifat Imtiaz Mohammad
Published: January 2018

Purpose

This paper aims to provide a comparative discussion on silence as a misrepresentation in contractual obligations between common law and Islamic law. The objective of this paper is to – from a legal pluralism point of view – highlight the contrasts between the two traditions and provide recommendations for best practices to achieve fairness and equity among the contracting parties. While common law does not treat silence as conscious misrepresentation, in Islamic law, silence does not constitute affirmative will. This has repercussions for the contracting parties because if future disputes arise, the aggrieved party in Islamic law reserves the option to rescind or nullify the contract – an opportunity not afforded by common law. We have discussed and analyzed the implementations of the different contractual terms, such as fraud, misrepresentation, trickery and deception in relation with Islamic law principles and common law practices. This research is an effort to draw the attention for further development in both Islamic law and common law practices on contractual obligation. The notion of misrepresentation – subset of a broader gamut of fraud – is arguably nebulous in Islamic literature as well. We delve into these nuances and provide examples both from common law and Islamic law precedents and provide recommendations for reform in both traditions.

Design/methodology/approach

This paper operates under qualitative methodological framework and uses secondary sources for analysis. Sources include journal databases, review of cases, classical/medieval Islamic scripts, etc.

Findings

This paper provides a general comparative study between common law’s principle and practice and Islamic law’s principle to forge a better understanding of fine-tuning existing practice and contribute to the debate on determining the best practices to unify international trade and custom exercise. Common law principle, obviously, holds a historical and traditional reputation as those principles are derived from long years of practice and judicial interpretation. Such historical legal system should accommodate fresh ideas in their repertoire and welcome novel ideas which would positively influence its own practice. This paper affords the freedom to the reader to interpret which general principle is acceptable in terms of contractual obligation.

Originality/value

Previous works exist on the issue of misrepresentation. However, those are mostly explanations of fraud and deceit in Islamic law or common law. The treatment of silence as affirmative will is seldom touched upon. To the authors’ knowledge, this is the first attempt at contrasting the treatment of silence in common and Islamic law. They have also advocated pluralistic practices and argued for legal reform whereby both traditions can benefit from each other.
Supply chain strategies in an era of natural resource scarcity
Authors: Kalaitzi Dimitra , Matopoulos Aristides , Bourlakis Michael , Tate Wendy
Published: January 2018

Purpose

The purpose of this paper is to explore the implications of natural resource scarcity (NRS) for companies’ supply chain strategies.

Design/methodology/approach

Drawing on the resource dependence theory (RDT), a conceptual model is developed and validated through the means of exploratory research. The empirical work includes the assessment of qualitative data collected via 22 interviews representing six large multinational companies from the manufacturing sector.

Findings

When the resources are scarce and vitally important, companies use buffering strategies. Buffering and bridging strategies are preferred when there are a few alternative suppliers for the specific resource and when there is limited access to scarce natural resources.

Research limitations/implications

The research focuses on large multinational manufacturing companies so results may not be generalised to other sectors and to small- and medium-sized firms. Future research needs to examine the implications of NRS for organisational performance.

Practical implications

This research provides direction to manufacturing companies for adopting the best supply chain strategy to cope with NRS.

Originality/value

This paper adds to the body of knowledge by providing new data and empirical insights into the issue of NRS in supply chains. The RDT has not been previously employed in this context. Past studies are mainly conceptual and, thus, the value of this paper comes from using a qualitative approach on gaining in-depth insights into supply chain-related NRS strategies and its antecedents.