bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathologic Oxidation of PTPN12 Underlies ABL1 Phosphorylation in Hereditary Leiomyomatosis and Renal Cell Carcinoma
Authors: Xu Yang , Taylor Paul , Andrade Joshua , Ueberheide Beatrix , Shuch Brian , Glazer Peter M. , Bindra Ranjit S. , Moran Michael F. , Linehan W. Marston , Neel Benjamin G. 
Published: October 2018

Abstract

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an inherited cancer syndrome associated with a highly aggressive form of type 2 papillary renal cell carcinoma (PRCC). Germline inactivating alterations in fumarate hydratase (FH) cause HLRCC and result in elevated levels of reactive oxygen species (ROS). Recent work indicates that FH−/− PRCC cells have increased activation of ABL1, which promotes tumor growth, but how ABL1 is activated remains unclear. Given that oxidation can regulate protein-tyrosine phosphatase (PTP) catalytic activity, inactivation of an ABL-directed PTP by ROS might account for ABL1 activation in this malignancy. Our group previously developed “q-oxPTPome,” a method that globally monitors the oxidation of classical PTPs. In this study, we present a refined q-oxPTPome, increasing its sensitivity by &gt;10×. Applying q-oxPTPome to FH-deficient cell models showed that multiple PTPs were either highly oxidized (including PTPN12) or overexpressed. Highly oxidized PTPs were those with relatively high sensitivity to exogenous H2O2. Most PTP oxidation in FH-deficient cells was reversible, although nearly 40% of PTPN13 was irreversibly oxidized to the sulfonic acid state. Using substrate-trapping mutants, we mapped PTPs to their putative substrates and found that only PTPN12 could target ABL1. Furthermore, knockdown experiments identified PTPN12 as the major ABL1 phosphatase, and overexpression of PTPN12 inhibited ABL1 phosphorylation and HLRCC cell growth. These results show that ROS-induced oxidation of PTPN12 accounts for ABL1 phosphorylation in HLRCC-associated PRCC, revealing a novel mechanism for inactivating a tumor suppressor gene product and establishing a direct link between pathologic PTP oxidation and neoplastic disease.

Significance:
This work identifies a novel mechanism of activation of the oncogenic kinase ABL1 via ROS-induced, oxidation-mediated inactivation of cognate protein tyrosine phosphatases.
Relationship between Circulating Inflammation Proteins and Lung Cancer Diagnosis in the National Lung Screening Trial
Authors: Brown Derek , Zingone Adriana , Yu Yunkai , Zhu Bin , Candia Julián , Cao Liang , Ryan Bríd M. 
Published: October 2018

Abstract

Background:
Previously, we observed a strong relationship between circulating serum inflammation proteins in relation to lung cancer diagnosis and risk, both in case–control and prospective cohorts. Low-dose computed tomography (LDCT) screening has a high prevalence of false-positive nodules, thus companion noninvasive biomarkers that can distinguish between benign and malignant nodules could have clinical utility and positive impact on patient outcomes.

Methods:
We conducted a nested case–control study within the National Lung Screening Trial. Concentrations of 30 inflammation proteins were measured on plasma samples of 262 cases and 528 controls using a highly sensitive and analytically validated electrochemiluminescence V-PLEX immunoassay.

Results:
Comparing the fourth quartile with the first quartile, we found increased IFNγ and IL12/IL23p40 associated with increased odds of a lung cancer diagnosis [OR 1.89, 95% confidence intervals (CI), 1.16–3.09; OR 2.49, 95% CI, 1.46–4.23, respectively]. Confirming our previous observations, we also detected a relationship between increased IL6, IL8, and C-reactive protein (CRP) with lung cancer diagnosis. These relationships were significant after adjustment for age, gender, race, smoking, body mass index (BMI), family history of lung cancer, and previous diagnoses of inflammatory conditions. However, none of these proteins could distinguish between a benign and malignant lung nodule (IL6: OR 1.25, 95% CI, 0.59–2.64; IL8: OR 1.40, 95% CI, 0.70–2.81; CRP: OR 0.98, 95% CI, 0.45–2.12).

Conclusions:
We have discovered new associations for IFNγ and IL12/IL23p40 with lung cancer but have no evidence that these proteins can distinguish between benign and malignant lung nodules.

Impact:
Circulating inflammation proteins are unlikely to have utility as companion LDCT biomarkers.
Long-Term Survival in Patients Responding to Anti–PD-1/PD-L1 Therapy and Disease Outcome upon Treatment Discontinuation
Authors: Gauci Marie-Léa , Lanoy Emilie , Champiat Stéphane , Caramella Caroline , Ammari Samy , Aspeslagh Sandrine , Varga Andrea , Baldini Capucine , Bahleda Rastilav , Gazzah Anas , Michot Jean-Marie , Postel-Vinay Sophie , Angevin Eric , Ribrag Vincent , Hollebecque Antoine , Soria Jean-Charles , Robert Caroline , Massard Christophe , Marabelle Aurélien 
Published: October 2018

Abstract

Purpose:
Anti–PD-(L)1 can provide overall survival (OS) benefits over conventional treatments for patients with many different cancer types. However, the long-term outcome of cancer patients responding to these therapies remains unknown. This study is an exploratory study that aimed to describe the long-term survival of patients responding to anti–PD-(L)1 monotherapy across multiple cancer types.
Patients and Methods: Data from patients treated with an anti–PD-(L)1 monotherapy in a phase I trial at Gustave Roussy were retrospectively analyzed over a period of 5 years. All cancer types (n = 19) were included. Clinical and biological factors associated with response, long-term survival, and secondary refractory disease were studied.

Results:
Among 262 eligible patients, the overall objective response rate was 29%. The median progression-free survival of responder patients (RP) at 3 months was 30 months, and the median OS of RP was not reached after a median follow-up of 34 months. In RPs, 3- and 5-year OS percentages were 84% and 64%, respectively. No death occurred in the 21 complete responders (CR) during the overall follow-up. However, many partial responders (PR) showed subsequent tumor relapses to treatment. Long responders (response ≥2 years) represented 11.8% of the overall population. These findings should be validated in further prospective studies.

Conclusions:
There are currently no differences in therapeutic strategies between CRs and PRs to anti–PD-(L)1. We found a striking difference in OS between these two types of responses. Our results are in favor of evaluating patient stratification strategies and intensification of treatments when tumor lesions of a partial responder to immunotherapy stop improving.
See related commentary by Cohen and Flaherty, p. 910
AXL Is a Putative Tumor Suppressor and Dormancy Regulator in Prostate Cancer
Authors: Axelrod Haley D. , Valkenburg Kenneth C. , Amend Sarah R. , Hicks Jessica L. , Parsana Princy , Torga Gonzalo , DeMarzo Angelo M. , Pienta Kenneth J. 
Published: October 2018

Abstract

Prostate cancer bone metastasis remains lethal and incurable, and often arises years after elimination of the primary tumor. It is unclear what underlies the decades-long clinical latency before recurrence, but evidence points to the existence of dormant residual tumor cells that disseminated before the primary tumor was eliminated. To design therapies to prevent progression of disseminated tumor cells (DTC) into lethal metastases, it is crucial to understand the mechanism(s) underlying this dormancy. The current study functionally validated our previous observation that implicated the GAS6/AXL axis in mediating DTC dormancy in the bone marrow. AXL-null and AXL-overexpressing prostate cancer cell lines were generated to determine if AXL was necessary and/or sufficient for dormancy. Characterization of these cells in vitro and using in vivo mouse models of DTC growth demonstrated that AXL was indeed sufficient to induce dormancy, but was unable to maintain it long-term and was not absolutely required for a dormancy period. Clinically, AXL expression correlated with longer survival in prostate cancer patients, and AXL was not expressed by cancer cells in primary or metastatic tissue. These data point to a tumor-suppressive role for AXL in prostate cancer, and future work is required to determine if AXL is expressed on human bone marrow DTCs.

Implications:
The ability of AXL to initiate but not maintain dormancy, coupled with its dispensability, suggests that targeting AXL alone will not prevent lethal metastatic outgrowth, and likely a cooperative network of factors exists to mediate long-term cellular dormancy.
Genetic Modifiers for the Long-QT Syndrome
Authors: Crotti Lia , Lahtinen Annukka M. , Spazzolini Carla , Mastantuono Elisa , Monti Maria Cristina , Morassutto Caterina , Parati Gianfranco , Heradien Marshall , Goosen Althea , Lichtner Peter , Meitinger Thomas , Brink Paul A. , Kontula Kimmo , Swan Heikki , Schwartz Peter J. 
Published: October 2018

Background—

Long-QT syndrome is an inherited cardiac channelopathy characterized by delayed repolarization, risk of life-threatening arrhythmia, and significant clinical variability even within families. Three single-nucleotide polymorphisms (SNPs) in the 3′ untranslated region of
KCNQ1
were recently suggested to be associated with suppressed gene expression and hence decreased disease severity when located on the same haplotype with a disease-causing
KCNQ1
mutation. We sought to replicate this finding in a larger and a genetically more homogeneous population of
KCNQ1
mutation carriers.

Methods and Results—

The 3 SNPs (rs2519184, rs8234, and rs10798) were genotyped in a total of 747
KCNQ1
mutation carriers with A341V, G589D, or IVS7-2A>G mutation. The SNP haplotypes were assigned based on family trees. The SNP allele frequencies and clinical severity differed between the 3 mutation groups. The different SNP haplotypes were neither associated with heart rate–corrected QT interval duration (QTc) nor cardiac events in any of the 3 mutation groups. When the mutation groups were combined, the derived SNP haplotype of rs8234 and rs10798 located on the same haplotype with the mutation was associated with a shorter QTc interval (
P
<0.05) and a reduced occurrence of cardiac events (
P
<0.01), consistent with the previous finding. However, when the population-specific mutation was controlled for, both associations were no longer evident.

Conclusions—
3′ Untranslated region SNPs are not acting as genetic modifiers in a large group of LQT1 patients. The confounding effect of merging a genetically and clinically heterogeneous group of patients needs to be taken into account when studying disease modifiers.
Abstract TP18: Interventional Management of Carotid Occlusions in the Setting of Acute Stroke: An Experience at a Busy Comprehensive Stroke Center
Authors: Boutwell Christine M , Olds Karin , Akhtar Iqra , Martin Coleman , Holloway William , Akhtar Naveed 
Published: October 2018

Introduction:
Carotid artery occlusion in the setting of acute stroke with concurrent intracranial involvement is a serious and deadly combination, and can prove to be a challenging endeavor when encountered. The stroke is usually more severe due to poor collaterals and successful revascularization is difficult to achieve, resulting in a higher morbidity and mortality. We aim to assess the revascularization rates and clinical outcomes in this subset of patients treated with endovascular therapy.

Methods:
An IRB approved retrospective chart review of cases presenting with acute ischemic stroke with carotid occlusions and concurrent intracranial involvement treated with endovascular therapy over a 4-year period was conducted. Of these reviewed cases, 75 patients had carotid occlusions with intracranial involvement. The carotid T occlusions and critical ICA stenosis with intracranial flow were excluded from the study.

Based on the CT and catheter angiogram findings, the 75 patients fell into two groups:
1) Group A (n=35): Carotid occlusion with underlying atherosclerotic disease/dissection resulting in occlusion and were treated with angioplasty and stenting followed by thrombus retrieval.
2) Group B (n=40): No underlying pathology was found and ICA was occluded due to a large embolus to the ICA with no anterograde flow in the ICA. This group was treated with thrombus retrieval alone.

Results:
Our data shows that the presence of a stent in the ICA does not adversely affect the intracranial recanalization rate (91.4% TICI
≥
2b). There was also no significant increase in hemorrhage rate with revascularization and antiplatelet therapy (2.9%). This finding was especially significant due to the large amount of wake up strokes in our study that were treated with intervention (17.3%). The successful reperfusion rate (TICI ≥2b) overall in both groups was 82.7%. In the successfully recanalized group, the mortality was 16% compared to the mortality in the unsuccessfully recanalized group (69.2%).

Conclusions:
Our study results show that it is possible to achieve a high success rate of revascularization and clinical outcomes with an endovascular approach to managing carotid occlusion with intracranial involvement.
Abstract TP263: Activation of Endothelial p21-Activated Kinase 1 Provides Neuroprotection After Stroke
Authors: Liu Lin , Sun Ping , Yi Yanhua , Spahr Zachary R , McCullough Louise , Li Jun 
Published: October 2018

Stroke is a major cause of death and long-term disability. Pak1 is implicated in many neurological disorders as it has been suggested to promote neuronal survival. However, its function and mechanisms have not been investigated in stroke. We assessed the hypothesis that Pak1 provides neuroprotection in stroke by stimulating the secretion of brain-derived neurotrophic factor (BDNF) in endothelial cells.
Transient focal ischemia was induced by middle cerebral artery occlusion (MCAO, 90 mins) in young WT male mice. Two doses of IPA3, a Pak1 specific inhibitor, were injected (i.p.) at 30 minutes prior to stroke and 1.5 hours after stroke. For mechanism studies, lentivirus (LV) encoding Pak1 or IPA3 was used to overexpress or pharmacologically inhibit Pak1 in mouse primary brain microvascular endothelial culture. Then the cells were subjected to OGD (16h) with 48 h re-oxygenation and conditioned media (Endo-CM) were collected subsequently. Mouse primary cortical neuron culture was treated with Endo-CM after OGD (90 mins) and neuronal death was assessed 24 hours later.
Pak1 activation (phosphorylated Pak1) was observed in the ischemic hemispheres 6 and 72 hours after MCAO (p-Pak1: sham 94.5± 4.7% versus 6-hour stroke 192.5 ± 10.4% ; sham 94.5± 4.7% versus 72-hour stroke 254.4 ± 32.3%, n = 4 p/g, p<0.05 for both). Administration of IPA3 increased brain infarct size assessed 24 hours after MCAO stroke. In endothelial cultures, overexpression of Pak1 increased BDNF secretion in Endo-CM after OGD (LV-GFP 22.7 ± 2.8 versus LV-Pak1 48.6± 5.5, n = 4 p/g, p<0.05). Accordingly, inhibition of Pak1 attenuated levels of BDNF in Endo-CM (Vehicle 24.5 ± 1.5 versus IPA3 9.4± 0.7, n = 3 p/g, p<0.05). Finally, treatment with Endo-CM collected from Pak1 overexpressing culture reduced neuronal death after OGD (LV-GFP 36 ± 2% versus LV-Pak1 10± 1%, n = 3 p/g, p<0.05), while Endo-CM from cells treated with Pak1 inhibitor increased neuronal mortality (Vehicle 24± 7% versus IPA3 43± 2%, n = 3 p/g, p<0.05).
Taken together, we demonstrated that endothelial Pak1 provides neuroprotection after ischemia. Mechanically, our data revealed that activation of Pak1 stimulates endothelial production of a well-known potent neuroprotectant, BDNF.
Sensorless balance method for the spindle system of computer numerical control gear grinding machine
Authors: Li Yong , Zhou Shaoping 
Published: October 2018

Background: Spindle imbalance vibration of the computer numerical control grinding machine may result in dramatic effects on tool wear, surface finish, and form-holding of the products, which makes the balancing procedure very essential during their manufacturing process. Although the spindle residual vibration in a single direction can be suppressed effectively by the commonly used commercial balance systems, some real-world application results show that most of these balance systems cannot reduce the spindle residual vibration in horizontal, vertical, and axial direction simultaneously. Methods: To overcome this issue, the limitation of commonly used influence coefficient method–based spindle balance method is discussed first. After that, a novel balance method is experimentally proposed for the spindle vibration control using the position fluctuation information between the carriage and guideway of the servo-axis. In this method, the position fluctuation information between the carriage and guideway and the key phase information are practically measured using the built-in linear scale and spindle servomotor encoder, respectively, in which the position fluctuation information between the carriage and guideway can be considered as an integrated representation of the spindle imbalance vibration. Combined with the influence coefficient method, the imbalance vibration presenting in the horizontal, vertical, and axial direction of the spindle can be suppressed simultaneously and effectively. Results and Conclusions: A field balancing experiment is carried out on a high-precision computer numerical control gear grinding machine. Experiment results demonstrate that, compared with the commonly used commercial balancing system, the proposed method can not only reduce the residual vibration amplitude at the objective balancing speed effectively but also reduce the residual vibration amplitude more than 50% simultaneously in each direction during the whole run-down process.
Interobserver agreement and the effects of ethnicity on observational coding of affect
Authors: Babcock Julia C. , Banks Josilyn C. 
Published: October 2018

Objectives: The Specific Affect Coding System (SPAFF) is a reliable system for coding observed affect but few studies have tested its generalizability and susceptibility to bias. Methods: The current study compared highly trained African American and Caucasian coders’ scores when coding the same videos of African American and Caucasian American couples. Results: While it was hypothesized that Caucasian Americans may code African America couples as being more aggressive and less positive based on stereotypes, results revealed a significant Ethnicity of Coder × Ethnicity of Couple interaction on the “neutral” code only. Both African American and Caucasian coders tended to rate out-group couples as being less neutral and showing less interest than in-group couples. No other emotion was identified as being over-coded in lieu of neutral, however. Conclusion: Results suggest a subtle bias in SPAFF coding. Adding a diversity component to the SPAFF training and recruiting diverse coders is recommended.
Dental age assessment on panoramic radiographs: Comparison between two generations of young Finnish subjects
Authors: Birchler Flavia A. , Kiliaridis Stavros , Combescure Christophe , Julku Johanna , Pirttiniemi Pertti M. , Vazquez Lydia 
Published: October 2018

Objective To analyse the accuracy of a meta-analysis-based dental age assessment (DAA) method in Finnish paediatric patients and to compare the dental development between two generations of Finnish children. Methods Panoramic radiographs of Finnish Caucasian healthy children from two generations (early: born 1981–1984; subsequent: born 1996–2008) were analysed. All developing teeth on the left maxilla and mandible as well as the third permanent molars were analysed following Demirjian’s classification. For each patient, dental age was calculated and compared with chronological age. Dental maturation patterns between the two groups were compared. Results The study included 200 Finnish Caucasian healthy children from two generations (early: aged 7–13 years; subsequent: aged 6–15 years). In the early generation, DAA underestimated the chronological age by a mean of 3.15 years. The underestimation was only 0.11 years in patients < 10 years, but 3.86 years in patients ≥ 10 years. In the subsequent generation, the dental age was overestimated by a mean of 0.34 years; by 0.40 years in patients < 10 years and by 0.08 years in patients ≥ 10 years. Conclusions The present DAA method is applicable to current Finnish children. Differences in dental development between two generations of Finnish children were detected.
Assessment of Bony Subfibular Impingement in Flatfoot Patients Using Weight-Bearing CT Scans
Authors: Jeng Clifford L. , Rutherford Tyler , Hull Michael G. , Cerrato Rebecca A. , Campbell John T. 
Published: October 2018

Background: Lateral hindfoot pain in patients with flatfoot deformity is frequently attributed to subfibular impingement. It remains unclear whether this is primarily due to bony or soft-tissue impingement. No studies have used weight-bearing CT scans to evaluate subfibular impingement. Methods: Patients with posterior tibial tendonitis were retrospectively searched and reviewed. Subjects had documented flatfoot deformity, posterior tibial tenderness, weight-bearing plain radiographs, and a weight-bearing CT scan. CT scans were evaluated for calcaneofibular impingement on the coronal view and talocalcaneal impingement on the sagittal view. The distance between these structures was measured, along with the sinus tarsi volume. In the second part of this study, 6 normal volunteers underwent weight-bearing CT scans on a platform that held both feet in 20 degrees of varus, followed by 20 degrees of valgus. The same measurements were performed. Results: Thirty-five percent of flatfoot patients with posterior tibial tendonitis had bony impingement between the fibula and calcaneus on the coronal view. Thirty-eight percent had bony impingement between the talus and calcaneus on the sagittal view. Subjects with bony impingement based on CT scan had significantly higher talonavicular abduction angles on plain radiographs than those without impingement. Sinus tarsi volume decreased by more than half when the subtalar joint moved from varus to valgus in normal controls. Conclusion: Bony subfibular impingement in patients with flatfeet was less common than previously reported. Accurate diagnosis of bony impingement may be useful for surgical decision-making. Level of Evidence: Level III, retrospective comparative study.
In vitro bactericidal activity of 0.6% povidone-iodine eye drops formulation
Authors: Musumeci Rosario , Bandello Francesco , Martinelli Marianna , Calaresu Enrico , Cocuzza Clementina Elvezia 
Published: October 2018

Purpose: To evaluate the bactericidal activity of a diluted povidone-iodine formulation (0.6%) in comparison with the most used 5% povidone-iodine solution ophthalmic preparation. Methods: In vitro bactericidal activity comparison between 0.6% povidone-iodine versus 5% povidone-iodine formulations, against these bacteria: Staphylococcus aureus ATCC 25923, Staphylococcus aureus ATCC 43300, Staphylococcus epidermidis ATCC 12228, linezolid-resistant Staphylococcus epidermidis α99 strain, a clinical isolate, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922. Results: About 0.6% povidone-iodine formulation was demonstrated to be faster than 5% povidone-iodine preparation in killing Gram-positive as well as Gram-negative bacteria. Against a linezolid-resistant methicillin-resistant Staphylococcus epidermidis strain, 0.6% povidone-iodine formulation showed the best antiseptic efficacy requirement of 3-log10 reduction in bacterial load, if compared with the 5% povidone-iodine formulation. Conclusion: Our investigation has demonstrated that the more diluted 0.6% preparation was more rapidly bactericidal than the 5% povidone-iodine formulation, most probably due to the fact that dilution from 5% to 0.6% increases the amount of free iodine. While our finding must be confirmed by in vivo clinical studies, this fact constitutes an intriguing news for what concerns the use of povidone-iodine eye drops in the ocular surface treatment before intravitreal injections as well as ophthalmic surgery.