bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Predictive ERBB Mutations by Leveraging Publicly Available Cell Line Databases
Authors: Koivu Marika K.A. , Chakroborty Deepankar , Tamirat Mahlet Z. , Johnson Mark S. , Kurppa Kari J. , Elenius Klaus 
Published: December 2020

Abstract
Although targeted therapies can be effective for a subgroup of patients, identification of individuals who benefit from the treatments is challenging. At the same time, the predictive significance of the majority of the thousands of mutations observed in the cancer tissues remains unknown. Here, we describe the identification of novel predictive biomarkers for ERBB-targeted tyrosine kinase inhibitors (TKIs) by leveraging the genetic and drug screening data available in the public cell line databases: Cancer Cell Line Encyclopedia, Genomics of Drug Sensitivity in Cancer, and Cancer Therapeutics Response Portal. We assessed the potential of 412 ERBB mutations in 296 cell lines to predict responses to 10 different ERBB-targeted TKIs. Seventy-six ERBB mutations were identified that were associated with ERBB TKI sensitivity comparable with non–small cell lung cancer cell lines harboring the well-established predictive EGFR L858R mutation or exon 19 deletions. Fourteen (18.4%) of these mutations were classified as oncogenic by the cBioPortal database, whereas 62 (81.6%) were regarded as novel potentially predictive mutations. Of the nine functionally validated novel mutations, EGFR Y1069C and ERBB2 E936K were transforming in Ba/F3 cells and demonstrated enhanced signaling activity. Mechanistically, the EGFR Y1069C mutation disrupted the binding of the ubiquitin ligase c-CBL to EGFR, whereas the ERBB2 E936K mutation selectively enhanced the activity of ERBB heterodimers. These findings indicate that integrating data from publicly available cell line databases can be used to identify novel, predictive nonhotspot mutations, potentially expanding the patient population benefiting from existing cancer therapies.
Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Antitumor T-cell Immunity
Authors: Hong Aayoung , Piva Marco , Liu Sixue , Hugo Willy , Lomeli Shirley H. , Zoete Vincent , Randolph Christopher E. , Yang Zhentao , Wang Yan , Lee Jordan J. , Lo Skylar J. , Sun Lu , Vega-Crespo Agustin , Garcia Alejandro J. , Shackelford David B. , Dubinett Steven M. , Scumpia Philip O. , Byrum Stephanie D. , Tackett Alan J. , Donahue Timothy R. , Michielin Olivier , Holmen Sheri L. , Ribas Antoni , Moriceau Gatien , Lo Roger S. 
Published: December 2020

Abstract

MAPK targeting in cancer often fails due to MAPK reactivation. MEK inhibitor (MEKi) monotherapy provides limited clinical benefits but may serve as a foundation for combination therapies. Here, we showed that combining a type II RAF inhibitor (RAFi) with an allosteric MEKi durably prevents and overcomes acquired resistance among cancers with KRAS, NRAS, NF1, BRAFnon-V600, and BRAFV600 mutations. Tumor cell–intrinsically, type II RAFi plus MEKi sequester MEK in RAF complexes, reduce MEK/MEK dimerization, and uncouple MEK from ERK in acquired-resistant tumor subpopulations. Immunologically, this combination expands memory and activated/exhausted CD8+ T cells, and durable tumor regression elicited by this combination requires CD8+ T cells, which can be reinvigorated by anti–PD-L1 therapy. Whereas MEKi reduces dominant intratumoral T-cell clones, type II RAFi cotreatment reverses this effect and promotes T-cell clonotypic expansion. These findings rationalize the clinical development of type II RAFi plus MEKi and their further combination with PD-1/L1-targeted therapy.

Significance:
Type I RAFi + MEKi are indicated only in certain BRAFV600MUT cancers. In contrast, type II RAFi + MEKi are durably active against acquired MEKi resistance across broad cancer indications, which reveals exquisite MAPK addiction. Allosteric modulation of MAPK protein/protein interactions and temporal preservation of intratumoral CD8+ T cells are mechanisms that may be further exploited.
This article is highlighted in the In This Issue feature, p. 521
Rediscovery of Caracal Caracal caracal (Schreber, 1776) (Mammalia: Carnivora: Felidae) in Abu Dhabi Emirate, UAE
Authors: Gubiani Robert , Al Zaabi Rashed , Chuven Justin , Soorae Pritpal 
Published: December 2020

We present evidence confirming the presence of Caracal Caracal caracal in Abu Dhabi Emirate. Camera trap deployment into areas likely to harbour elusive species revealed the presence of at least one male individual with 37 records in 683 camera trap days over a seven-month period. These records represent the first confirmed presence of Caracal in Abu Dhabi Emirate since 1965. Both diurnal and nocturnal records highlighted varied activity patterns of this generally elusive species. Foraging activity occurred primarily during low luminosity levels associated with the new moon. The evidence obtained proves the presence of Arabian Caracal in a location long suspected of providing suitable habitat for this species.
U.S. Pacific Coastal Droughts Are Predominantly Driven by Internal Atmospheric Variability
Authors: Baek Seung H. , Smerdon Jason E. , Cook Benjamin I. , Williams A. Park 
Published: December 2020

AbstractDroughts that span the states of Washington, Oregon, and California are rare but devastating due to their large spatial coverage and potential loss of redundancies in water, agricultural, and fire-fighting resources. Such pan-coastal droughts [which we define using boreal summer volumetric soil moisture along the U.S. Pacific coast (32°–50°N, 115°–127°W)] require a more precise understanding of the roles played by the Pacific Ocean and internal atmospheric variability. We employ 16-member ensembles of the Community Atmosphere Model version 5 and Community Climate Model version 3 forced with observed sea surface temperatures (SSTs) from 1856 to 2012 to separate and quantify the influences of the tropical Pacific and internal atmospheric variability on pan-coastal droughts; all other boundary conditions are kept at climatological levels to explicitly isolate for the impacts of SST changes. Internal atmospheric variability is the dominant driver of pan-coastal droughts, accounting for 84% of their severity, and can reliably generate pan-coastal droughts even when ocean conditions do not favor drought. Cold phases of the Pacific Ocean play a secondary role and contribute, on average, only 16% to pan-coastal drought severity. Spatiotemporal analyses of precipitation and soil moisture along the U.S. Pacific coast corroborate these findings and identify an antiphased wet–dry dipole pattern induced by the Pacific to play a more secondary role. Our model framework expands on previous observational analyses that point to the spatially uniform forcing of internal atmospheric variability as the more dominant mode of hydroclimate variability along the U.S. Pacific coast. The secondary nature of oceanic forcing suggests limited predictability of pan-continental droughts.
Pattern of thermal damage and tissue carbonisation from endovenous radiofrequency ablation catheter – Using an in vitro porcine liver model
Authors: Dabbs Emma B , Riley Max I , Davies Charlotte E , Bishop Olivia H , Whiteley Mark S 
Published: December 2020

Background Successful endovenous thermoablation relies on transmural vein wall ablation. We investigated the pattern of thermal spread and tissue carbonisation from RadioFrequency-induced ThermoTherapy (RFiTT) at different powers and pull back methods, using a porcine liver model. Methods We used a previously validated in-vitro porcine liver model. Different powers from 5–25 W were used to administer 150 J. We compared continuous and pulsed energy delivery. Length, lateral spread, and total area of thermal damage, together with any tissue carbonisation, was measured using digital analysis software. Results All experiments used 150 J total energy. Total thermal damage area was smaller with lower power and pulsed energy. Continuous energy caused more tissue carbonisation than pulsed except at 25 W. Conclusion Reduced thermal damage with lower power or pulsed energy results from cooling due to increased time of treatment. Increasing the power increases tissue carbonisation. Optimal treatment is determined by the highest power used continuously that does not cause tissue carbonisation.
Mystical-type experiences occasioned by ketamine mediate its impact on at-risk drinking: Results from a randomized, controlled trial
Authors: Rothberg Rebecca L , Azhari Nour , Haug Nancy A , Dakwar Elias 
Published: December 2020

Background: Sub-anesthetic ketamine administration may be helpful for substance use disorders. Converging evidence suggests that the efficacy of ketamine for certain conditions may implicate a subset of its psychoactive effects. Aims: The aim of this analysis is to evaluate whether the mystical-type effects of ketamine are critical for clinical efficacy in alcohol-dependent individuals. In this secondary analysis, we determine if a subset of the psychoactive effects of ketamine, the so-called mystical-type experience, mediates the effect of ketamine, when combined with motivational enhancement therapy, on at-risk drinking behavior in alcohol-dependent individuals interested in treatment. Methods: Forty alcohol dependent adults were randomized to either a 52-minute infusion of ketamine or midazolam, which they received on a designated quit-day during the second week of a five-week motivational enhancement therapy regimen. Psychoactive effects were assessed following the infusion, and alcohol use was monitored for the subsequent 3 weeks at each twice-weekly visit. Results: We found that ketamine leads to significantly greater mystical-type effects (by Hood Mysticism Scale) and dissociation (by Clinician Administered Dissociative States Scale) compared to the active control. Ketamine also led to significant reduction in at-risk drinking. The Hood Mysticism Scale, but not Clinician Administered Dissociative States Scale score, was found to mediate the effect of ketamine on drinking behavior. Conclusions: This trial adds evidence to the literature on the importance of mystical-type experiences in addiction treatment. Future research should continue to investigate the relationship between the psychoactive effects of psychedelic therapeutics and clinical outcomes for other substance use and mental health disorders.
Percutaneous stent-in-stent placement with large cell-type stents for malignant hilar biliary obstruction
Authors: Kim Gun Ha , Gwon Dong Il , Ko Gi-Young , Kim Jin Hyoung , Kim Jong Woo , Chu Hee Ho , Yoon Hyun-Ki , Sung Kyu-Bo 
Published: December 2020

Background To overcome the technical difficulty of bilateral stent-in-stent placement, large cell-type biliary stents have been developed. However, most of the studies using large cell-type stents were conducted with endoscopic method. Purpose To evaluate the efficacy and safety of percutaneous stent placement with a stent-in-stent method using large cell-type stents in patients with malignant hilar biliary obstruction. Material and Methods From December 2015 and October 2018, 51 patients with malignant hilar biliary obstruction were retrospectively studied. All of the patients underwent bilateral (n=46) or unilateral (n=5) stenting in a T, Y, or X configuration with a stent-in-stent method using large cell-type stents. Technical success, complications, successful internal drainage, stent patency, and patient survival were analyzed. Results A total of 118 stents were successfully placed in 51 patients (100.0%). Three patients had minor complications with self-limiting hemobilia. Major complications were not observed in any patient. Successful internal drainage was achieved in 45 patients (88.2%). Clinical follow-up information until death or the end of the study was available for 50 of 51 patients. The median patient survival was 285.5 days (95% confidence interval [CI] 197–374). Stent dysfunction occurred in 16 patients (35.6%) due to tumor ingrowth (n=9) or tumor ingrowth combined with biliary sludge (n=7) among the patients who achieved successful internal drainage. Median stent patency was 179 days (95% CI 104–271). Conclusion Percutaneous stent-in-stent placement with large cell-type stents is technically feasible and safe, and can be an effective technique in patients with malignant hilar biliary obstruction.
Characterization of the Proximal Long Head of Biceps Tendon Anatomy Using Magnetic Resonance Imaging: Implications for Biceps Tenodesis
Authors: Ek Eugene T. , Philpott Andrew J. , Flynn Jennifer N. , Richards Nada , Hardidge Andrew J. , Rotstein Andrew H. , Wood Ayla D. 
Published: December 2020

Background: Biceps tenodesis is a common treatment for proximal long head of biceps (LHB) tendon pathology. To maintain biceps strength and contour and minimize cramping, restoration of muscle-length tension and appropriate positioning of the tenodesis is key. Little is known about the biceps musculotendinous junction (MTJ) anatomy, especially in relation to the overlying pectoralis major tendon (PMT), which is a commonly used landmark for tenodesis positioning. Purpose: To characterize the in vivo topographic anatomy of the LHB tendon, in particular the MTJ relative to the PMT, using a novel axial proton-density magnetic resonance imaging (MRI) sequence. Study Design: Descriptive laboratory study. Methods: In total, 45 patients having a shoulder MRI for symptoms unrelated to their biceps tendon or rotator cuff were prospectively recruited. There were 33 men and 12 women, with a mean age of 37 ± 13 years (range, 18-59 years). All patients underwent routine shoulder MRI scans with an additional axial proton density sequence examining the LHB tendon and its MTJ. Three independent observers reviewed each MRI scan, and measurements were obtained for (1) MTJ length, (2) the distance between the proximal MTJ and the superior border of the PMT (MTJ-S), (3) the distance between the distal MTJ to the inferior border of the PMT, and (4) the width of the PMT. Results: The average position of the MTJ-S was 5.9 ± 10.8 mm distal to the superior border of the PMT. The mean MTJ length was 32.5 ± 8.3 mm and the width of the PMT was 28.0 ± 7.3 mm. We found no significant correlation between patient age, height, sex, or body mass index and any of the biceps measurements. We observed wide variability of the MTJ-S position and identified 3 distinct types of biceps MTJ: type 1, MTJ-S above the PMT; type 2, MTJ-S between 0 and 10 mm below the superior border of the PMT; and type 3, MTJ-S >10 mm distal to the superior PMT. Conclusion: In this study, the in vivo anatomy of the LHB tendon is characterized relative to the PMT using a novel MRI sequence. The results demonstrate wide variability in the position of the MTJ relative to the PMT, which can be classified into 3 distinct subtypes or zones relative to the superior border of the PMT. Understanding this potentially allows for accurate and anatomic placement of the biceps tendon for tenodesis. Clinical Relevance: To our knowledge, this is the first study to radiologically analyze the in vivo topographic anatomy of the LHB tendon and its MTJ. The results of this study provide more detailed understanding of the variability of the biceps MTJ, thus allowing for more accurate placement of the biceps tendon during tenodesis.
Hemoglobin Target and Transfusion Modality for Adult Patients With Sickle Cell Disease Acute Chest Syndrome
Authors: Simonson Joseph L. , Rosentsveyg Juliana A. , Schwartz Noah G. , Agrawal Abhinav , Koenig Seth , Zaidi Gulrukh Z. 
Published: December 2020

Background: Despite the importance of transfusion in treating sickle cell disease acute chest syndrome, the target hemoglobin and optimal modality for transfusion remain unknown. Objectives: To compare hospital length of stay (LOS) in intensive care unit (ICU) patients with acute chest syndrome transfused to hemoglobin ≥ 8 g/dL versus patients transfused to hemoglobin < 8 g/dL; and to compare hospital LOS in acute chest syndrome patients treated with and without exchange transfusion. Methods: We performed a retrospective cohort study of all acute chest syndrome patients treated in the medical ICU at 2 tertiary care hospitals between January 2011 and August 2016 ( n = 82). We compared median hospital LOS in patients transfused to hemoglobin ≥ 8 g/dL by the time of ICU transfer to the medical floor versus patients transfused to hemoglobin < 8 g/dL as well as patients who received exchange transfusion versus no exchange transfusion using Wilcoxon rank-sum tests. We modeled the association between hospital LOS and hemoglobin at ICU transfer to the medical floor using multivariable log-linear regression. Results: Median hospital LOS was about half as long for patients transfused to hemoglobin ≥ 8 g/dL versus hemoglobin < 8 g/dL (8.0 versus 16.5 days, P = 0.008). There was no difference in LOS for patients treated with and without exchange transfusion. On average, a 1 g/dL increase in hemoglobin was associated with a 19.5% decrease (95% CI 10.8-28.2%) in LOS, controlling for possible confounding factors. Conclusions: Transfusion to a hemoglobin target ≥ 8 g/dL is associated with decreased hospital LOS in patients with acute chest syndrome. There was no difference in LOS between patients who received exchange transfusion and those who did not.
Serum vitamin D levels in patients with vernal keratoconjunctivitis and its relationship with disease severity
Authors: Sorkhabi Rana , Ahoor Mohammad Hosein , Ghorbanihaghjo Amir , Jafari Sasan 
Published: December 2020

Purpose To evaluate the serum vitamin D levels of patients with vernal keratoconjunctivitis (VKC) Method A total of 39 VKC patients (21 males and 18 females) and 32 healthy individuals (19 males and 13 females) were enrolled in this study with the mean age of 18.38 ± 8.83 and 21.6 ± 9.43, respectively. The type and the grade of VKC were identified for each patient and serum 25-hydroxyvitamin D (25(OH)D) levels of all subjects were evaluated. Results The patients affected by VKC had statistically significant lower 25(OH)D levels (27.64 ± 8.50 ng/mL) than healthy subjects group (35.96 ± 11.34 ng/mL) ( p = 0.001). A reverse correlation was found between the serum vitamin D levels and the severity of the VKC but it was not statistically significant ( r = −0.159, p = 0.33). Besides, there were a few cases with severe and very severe VKC (2 in grade 3 and 4 in grade 4). Patients with the mixed type of the disease had lower serum vitamin D levels in comparison to tarsal and limbal forms but the difference was not statistically significant ( p = 0.38). Conclusion This study shows that the patients affected by VKC have lower vitamin D levels in comparison to healthy subjects and the screening of all patients with VKC for vitamin D levels seems rational.
Reduction of Opioid Prescriptions in Maxillofacial Trauma Following North Carolina STOP Act
Authors: Curtis Caitrin , Scarcella Joshua , Viscardi Chelsea , Samia Arthur , Zeri Richard , Guo Yifan 
Published: December 2020

Study Design: Retrospective cohort study Objective: On January 1, 2018, the Strengthen Opioid Misuse Prevention (STOP) Act was implemented to increase oversight over opioid prescriptions in North Carolina. The aim of this study is to evaluate the legislation’s efficacy in reducing opioid prescriptions following facial fracture repair. Methods: A retrospective chart review of patients who sustained maxillofacial fractures and underwent repair from January 1, 2015 through December 31, 2019 at a level 1 trauma center was performed. The North Carolina Controlled Substance Database was used to quantify perioperative opioid prescriptions in morphine milligram equivalents (MME). Average MME per patient was compared between 2 groups, patients who underwent surgery before the NC STOP Act came into effect and patients who underwent treatment after. This comparison was also performed on case type subgroups including surgically treated fractures of the orbit, mandible, midface, and multiple regions. A student’s t-test was used to compare before and after groups in all analyses. Results: Of the 253 patients who met inclusion criteria, 146 were in the before group, and 107 were in the after group. There was a statistically significant, 30.9% decrease in overall average MME prescribed after the NC STOP Act was enacted. A statistically significant decrease was noted in patients who had facial fractures of multiple regions. Conclusion: Since the implementation of the NC STOP Act in 2018, there have been statistically and clinically significant decreases in the amount of opioids prescribed following surgical management of facial fractures.
BMP2 Is Required for Postnatal Maintenance of Osteochondral Tissues of the Temporomandibular Joint
Authors: O’Brien Mara H. , Dutra Eliane H. , Mehta Shivam , Chen Po-Jung , Yadav Sumit 
Published: December 2020

Objective Bone morphogenetic protein 2 (BMP2) plays important roles in cartilage growth and development. Paradoxically, elevated levels of BMP2 leads to hypertrophic differentiation and osteoarthritis of cartilage. We examined the in vivo loss of BMP2 in cells expressing aggrecan of the mandibular condyle and knee. Design Three-week-old BMP2 flox/flox- CreER-positive mice and their Cre-negative littermates were treated with tamoxifen and raised until 3 or 6 months. We also investigated the direct effects of BMP2 on chondrocytes in vitro. Cells from the mandibular condyle of mice were treated with recombinant human BMP2 (rhBMP2) or rhNoggin (inhibitor of BMP2 signaling). Results Conditional deletion of BMP2 caused breakage of the cartilage integrity in the mandibular condyle of mice from both age groups, accompanied by a decrease in cartilage thickness, matrix synthesis, mineralization, chondrocyte proliferation, and increased expression of degeneration markers, while the effects at articular cartilage were not significant. In vitro results revealed that rhBMP2 increased chondrocyte proliferation, mineralization, and differentiation, while noggin induced opposite effects. Conclusions In conclusion, BMP2 is essential for postnatal maintenance of the osteochondral tissues of the mandibular condyle.
The complexity of caregiving for community-living older adults with multiple chronic conditions: A qualitative study
Authors: Ploeg Jenny , Garnett Anna , Fraser Kimberly D , Baird Lisa Garland , Kaasalainen Sharon , McAiney Carrie , Markle-Reid Maureen , Dufour Sinéad 
Published: December 2020

Background:Older adults with multiple chronic conditions (MCC) rely heavily on caregivers for assistance with care. However, we know little about their psychosocial experiences and their needs for support in managing MCC. The purpose of this study was to explore the experiences of caregivers of older adults living in the community with MCC.Methods:This qualitative study was a secondary analysis of previously collected data from caregivers in Ontario and Alberta, Canada. Participants included caregivers of older adults (65 years and older) with three or more chronic conditions. Data were collected through in-depth, semi-structured interviews. Interview transcripts were coded and analyzed using Thorne’s interpretive description approach.Results:Most of the 47 caregiver participants were female (76.6%), aged 65 years of age or older (61.7%), married (87.2%) and were spouses to the care recipient (68.1%). Caregivers’ experiences of caring for community-living older adults with MCC were complex and included: (a) dealing with the demands of caregiving; (b) prioritizing chronic conditions; (c) living with my own health limitations; (d) feeling socially isolated and constrained; (e) remaining committed to caring; and (f) reaping the rewards of caregiving.Conclusions:Healthcare providers can play key roles in supporting caregivers of older adults with MCC by providing education and support on managing MCC, actively engaging them in goal setting and care planning, and linking them to appropriate community health and social support services. Communities can create environments that support caregivers in areas such as social participation, social inclusion, and community support and health services.