bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Combination of Trametinib and Ganitumab is Effective in RAS-Mutated PAX-Fusion Negative Rhabdomyosarcoma Models
Authors: Hebron Katie E. , Wan Xiaolin , Roth Jacob S. , Liewehr David J. , Sealover Nancy E. , Frye William J.E. , Kim Angela , Stauffer Stacey , Perkins Olivia L. , Sun Wenyue , Isanogle Kristine A. , Robinson Christina M. , James Amy , Awasthi Parirokh , Shankarappa Priya , Luo Xiaoling , Lei Haiyan , Butcher Donna , Smith Roberta , Edmondson Elijah F. , Chen Jin-Qiu , Kedei Noemi , Peer Cody J. , Shern Jack F. , Figg W. Douglas , Chen Lu , Hall Matthew D. , Difilippantonio Simone , Barr Frederic G. , Kortum Robert L. , Robey Robert W. , Vaseva Angelina V. , Khan Javed , Yohe Marielle E. 
Published: November 2022

Abstract

Purpose:
PAX-fusion negative rhabdomyosarcoma (FN RMS) is driven by alterations in the RAS/MAP kinase pathway and is partially responsive to MEK inhibition. Overexpression of IGF1R and its ligands is also observed in FN RMS. Preclinical and clinical studies have suggested that IGF1R is itself an important target in FN RMS. Our previous studies revealed preclinical efficacy of the MEK1/2 inhibitor, trametinib, and an IGF1R inhibitor, BMS-754807, but this combination was not pursued clinically due to intolerability in preclinical murine models. Here, we sought to identify a combination of an MEK1/2 inhibitor and IGF1R inhibitor, which would be tolerated in murine models and effective in both cell line and patient-derived xenograft models of RAS-mutant FN RMS.

Experimental Design:
Using proliferation and apoptosis assays, we studied the factorial effects of trametinib and ganitumab (AMG 479), a mAb with specificity for human and murine IGF1R, in a panel of RAS-mutant FN RMS cell lines. The molecular mechanism of the observed synergy was determined using conventional and capillary immunoassays. The efficacy and tolerability of trametinib/ganitumab was assessed using a panel of RAS-mutated cell-line and patient-derived RMS xenograft models.

Results:
Treatment with trametinib and ganitumab resulted in synergistic cellular growth inhibition in all cell lines tested and inhibition of tumor growth in four of six models of RAS-mutant RMS. The combination had little effect on body weight and did not produce thrombocytopenia, neutropenia, or hyperinsulinemia in tumor-bearing SCID beige mice. Mechanistically, ganitumab treatment prevented the phosphorylation of AKT induced by MEK inhibition alone. Therapeutic response to the combination was observed in models without a mutation in the PI3K/PTEN axis.

Conclusions:
We demonstrate that combined trametinib and ganitumab is effective in a genomically diverse panel of RAS-mutated FN RMS preclinical models. Our data also show that the trametinib/ganitumab combination likely has a favorable tolerability profile. These data support testing this combination in a phase I/II clinical trial for pediatric patients with relapsed or refractory RAS-mutated FN RMS.
Biology and Targetability of the Extended Spectrum ofPIK3CAMutations Detected in Breast Carcinoma
Authors: Rugo Hope S. , Raskina Kira , Schrock Alexa B. , Madison Russell W. , Graf Ryon P. , Sokol Ethan S. , Sivakumar Smruthy , Lee Jessica K. , Fisher Virginia , Oxnard Geoffrey R. , Tukachinsky Hanna 
Published: November 2022

AbstractPurpose:Alpelisib is a PI3K alpha (PI3Kα)-selective inhibitor approved for the treatment of hormone receptor–positive/HER2-negative (HR+/HER2−) PIK3CA-mutated advanced breast cancer (ABC) based on the SOLAR-1 trial, which defined 11 substitutions in exons 7, 9, and 20 in PIK3CA (SOLAR1m). We report alpelisib effectiveness for ABC harboring SOLAR1m, as well as other pathogenic PIK3CA mutations (OTHERm) using comprehensive genomic profiling (CGP).Experimental Design:A total of 33,977 tissue and 1,587 liquid biopsies were analyzed using hybrid capture–based CGP covering the entire coding sequence of PIK3CA. Clinical characteristics and treatment history were available for 10,750 patients with ABC in the deidentified Flatiron Health-Foundation Medicine clinico-genomic database (FH-FMI CGDB).Results:PIK3CAm were detected in 11,767/33,977 (35%) of tissue biopsies, including 2,300 (7%) samples with OTHERm and no SOLAR1m. Liquid biopsy had 77% sensitivity detecting PIK3CAm, increasing to 95% with circulating tumor DNA fraction ≥2%. In patients with HR+/HER2− ABC and PIK3CAm receiving alpelisib/fulvestrant (ALP+FUL; n = 182) or fulvestrant alone (FUL; n = 119), median real-world progression-free survival (rwPFS) was 5.9 months on ALP+FUL [95% confidence interval (CI): 5.1–7.4] versus 3.1 months on FUL (95% CI: 2.7–3.7; P &lt; 0.0001). In patients with OTHERm, median rwPFS was 4.0 months on ALP+FUL (95% CI: 2.8–10.1) versus 2.5 months on FUL (95% CI: 2.2–3.7; P = 0.0054).Conclusions:CGP detects diverse PIK3CAm in a greater number of patients with ABC than PCR hotspot testing; 20% of patients with PIK3CAm do not have SOLAR1m. These patients may derive benefit from alpelisib.See related commentary by Tau and Miller, p. 989
Substrate Ablation by Multivein, Multiballoon Coronary Venous Ethanol for Refractory Ventricular Tachycardia in Structural Heart Disease
Authors: Valderrábano Miguel , Fuentes Rojas Stephanie C. , Lador Adi , Patel Apoor , Schurmann Paul A. , Tapias Carlos , Rodríguez Diego , Carlos Sáenz Luis , Malahfji Maan , Shah Dipan J. , Mathuria Nilesh , Dave Amish S. 
Published: November 2022

Background:
Ablation of ventricular tachycardia (VT) in the setting of structural heart disease often requires extensive substrate elimination that is not always achievable by endocardial radiofrequency ablation. Epicardial ablation is not always feasible. Case reports suggest that venous ethanol ablation (VEA) through a multiballoon, multivein approach can lead to effective substrate ablation, but large data sets are lacking.

Methods:
VEA was performed in 44 consecutive patients with ablation-refractory VT (ischemic, n=21; sarcoid, n=3; Chagas, n=2; idiopathic, n=18). Targeted veins were selected by mapping coronary veins on the epicardial aspect of endocardial scar (identified by bipolar voltage <1.5 mV), using venography and signal recording with a 2F octapolar catheter or by guidewire unipolar signals. Epicardial mapping was performed in 15 patients. Vein segments in the epicardial aspect of VT substrates were treated with double-balloon VEA by blocking flow with 1 balloon while injecting ethanol through the lumen of the second balloon, forcing (and restricting) ethanol between balloons. Multiple balloon deployments and multiple veins were used as needed. In 22 patients, late gadolinium enhancement cardiac magnetic resonance imaged the VEA scar and its evolution.

Results:
Median ethanol delivered was 8.75 (interquartile range, 4.5–13) mL. Injected veins included interventricular vein (6), diagonal (5), septal (12), lateral (16), posterolateral (7), and middle cardiac vein (8), covering the entire range of left ventricular locations. Multiple veins were targeted in 14 patients. Ablated areas were visualized intraprocedurally as increased echogenicity on intracardiac echocardiography and incorporated into 3-dimensional maps. After VEA, vein and epicardial ablation maps showed elimination of abnormal electrograms of the VT substrate. Intracardiac echocardiography demonstrated increased intramural echogenicity at the targeted region of the 3-dimensional maps. At 1 year of follow-up, median of 314 (interquartile range, 198–453) days of follow-up, VT recurrence occurred in 7 patients, for a success of 84.1%.

Conclusions:
Multiballoon, multivein intramural ablation by VEA can provide effective substrate ablation in patients with ablation-refractory VT in the setting of structural heart disease over a broad range of left ventricular locations.
The Supply Side of Climate Policies: Keeping Unburnable Fossil Fuels in the Ground
Authors: Pellegrini Lorenzo , Arsel Murat 
Published: November 2022

Abstract
As the urgency of responding to climate change and the insufficiency of current demand-side policies to mitigate greenhouse gas emissions become clearer, supply-side initiatives are beginning to gain prominence and acceptance globally. Policies such as moratoria and compensation for leaving fossil fuels unextracted in exchange for financial compensation of rights owners are likely to be effective and complementary to existing policies. A number of unknowns remain regarding the operationalization of supply-side policies, such as how to establish a binding international agreement and how to raise and allocate financial compensation for nonextraction. Nevertheless, the need for supply-side policies only emphasizes the importance of imaginative and bold initiatives within the current conjuncture of global environmental politics.
Emerging Self-Representation Presents a Challenge When Perspectives Conflict
Authors: Yeung Emanuela , Askitis Dimitrios , Manea Velisar , Southgate Victoria 
Published: November 2022

Abstract
The capacity to take another’s perspective appears to be present from early in life, with young infants ostensibly able to predict others’ behaviour even when the self and other perspective are at odds. Yet, infants’ abilities are difficult to reconcile with the well-known problems that older children have with ignoring their own perspective. Here we show that it is the development of the self-perspective, at around 18 months, that creates a perspective conflict between self and other during a non-verbal perspective-tracking scenario. Using mirror self-recognition as a measure of self-awareness and pupil dilation to index conflict processing, our results show that mirror recognisers perceive greater conflict during action anticipation, specifically in a high inhibitory demand condition, in which conflict between self and other should be particularly salient.
Rethinking Forests Governance as Global Commons: Devolution of Quasi-Property Rights to Indigenous Communities
Authors: Lorenzini Sara 
Published: November 2022

Abstract
An increasing wave of « green capitalism » (Alper, 1993; Barron, 2005) undermines both environmental sustainability and democratic engagement worldwide: the forestry sector stands as a perfect example. Indeed, « green » policies like redd+ programmes and protected areas, often curb bottom-up participation and reduce forests’ multiple functions to the economic interests of few, contrarily to what the discourse on Sustainability calls for.
This paper aims to develop an alternative proposal for a multi-stakeholder model for forest governance that overcomes the public v. private dichotomy (Ostrom, 2010) and constitutes a tool for a broader approach to sustainability. By linking the discourse on the commons (Arnold, 1998; Agrawal & Ostrom, 1999; Hardin, 1968; Dietz, Ostrom and Stern, 2003; Dolsak, Ostrom & McKay, 2003; Ellickinson, 1993; Ostrom, 1990, 1999, 2005, 2010; Ostrom, Gardner and Walker, 1994; Ostrom&Ostrom, 1977) with the discourse on justice (Rawls, 1971; Sen, 1980, 1999, 2009; Anderson, 1999, 2010; Goodin, 1988), I construct an argument for a two-level social contract. Forest-dependent Indigenous communities are entitled with quasi-property rights as part of their capabilities set, so they may become trustees of the global forests. Evidences about the Yanesha peoples in Perù and the Binh Son villagers in Vietnam back up the argument that communities can establish micro-social conventions as a response to lands’ occupation and forests’ degradation.
This framework is aimed at both policy-makers and civil society to (i) justify and design decision- and policy-making and (ii) evaluate existing policies. Implementing it requires a paradigm shift from State-centred and neoliberal agenda towards innovative solutions in the name of sustainability and global justice.
The First 30 Years of GEWEX
Authors: Stephens Graeme , Polcher Jan , Zeng Xubin , van Oevelen Peter , Poveda Germán , Bosilovich Michael , Ahn Myoung-Hwan , Balsamo Gianpaolo , Duan Qingyun , Hegerl Gabriele , Jakob Christian , Lamptey Benjamin , Leung Ruby , Piles Maria , Su Zhongbo , Dirmeyer Paul , Findell Kirsten L. , Verhoef Anne , Ek Michael , L’Ecuyer Tristan , Roca Rémy , Nazemi Ali , Dominguez Francina , Klocke Daniel , Bony Sandrine 
Published: November 2022

Abstract
The Global Energy and Water Cycle Exchanges (GEWEX) project was created more than 30 years ago within the framework of the World Climate Research Programme (WCRP). The aim of this initiative was to address major gaps in our understanding of Earth’s energy and water cycles given a lack of information about the basic fluxes and associated reservoirs of these cycles. GEWEX sought to acquire and set standards for climatological data on variables essential for quantifying water and energy fluxes and for closing budgets at the regional and global scales. In so doing, GEWEX activities led to a greatly improved understanding of processes and our ability to predict them. Such understanding was viewed then, as it remains today, essential for advancing weather and climate prediction from global to regional scales. GEWEX has also demonstrated over time the importance of a wider engagement of different communities and the necessity of international collaboration for making progress on understanding and on the monitoring of the changes in the energy and water cycles under ever increasing human pressures. This paper reflects on the first 30 years of evolution and progress that has occurred within GEWEX. This evolution is presented in terms of three main phases of activity. Progress toward the main goals of GEWEX is highlighted by calling out a few achievements from each phase. A vision of the path forward for the coming decade, including the goals of GEWEX for the future, are also described.
Clinical Outcomes After Arthroscopic Pancapsular Shift for the Treatment of Multidirectional Glenohumeral Instability at a Mean Follow-up of 9 Years
Authors: Gruskay Jordan A. , Rakowski Dylan R. , Woolson Thomas E. , Horan Marilee P. , Millett Peter J. 
Published: November 2022

Background: Arthroscopic treatment of multidirectional instability (MDI) of the shoulder is being increasingly performed, but there is a paucity of studies with minimum 5-year follow-up. Purpose: To report on survivorship and patient-reported outcomes (PROs) after arthroscopic pancapsulorraphy (APC) for MDI with a minimum 5-year follow-up. Study Design: Case series; Level of evidence, 4. Methods: Institutional review board approval was obtained before initiation of this retrospective review of prospectively collected data. Patients were included if they had a minimum of follow-up 5 years after APC for MDI. PROs included the 12-Item Short Form Health Survey Physical Component Summary; American Shoulder and Elbow Surgeons; Single Assessment Numeric Evaluation; shortened version of Disabilities of the Arm, Shoulder and Hand; and patient satisfaction. Preoperative, short-term (1-2 years), and final follow-up PROs were compared. Recurrent instability, dislocation, and reoperation were collected, and survivorship analysis was performed. Results: A total of 49 shoulders in 44 patients (15 male, 29 female) treated between October 2005 and November 2015 were included in the study. MDI onset was atraumatic in 27 shoulders and traumatic in 22. Rotator interval closure was performed in 17 patients. Overall, 14 of 49 (29%) patients reported feelings of instability in the shoulder, of whom 5 (10.2%) underwent revision surgery at a mean of 1.5 years. Kaplan-Meier analysis demonstrated a survivorship rate of 88% at 5 years and 82% at 8 years, with failure defined as requiring revision surgery or postoperative feelings of instability with ASES score <65. Final outcome analysis was performed on 41 shoulders with a mean follow-up of 9.0 years (range, 5.1-14.6 years). All PROs demonstrated significant improvement from preoperative baseline ( P < .05) and remained significantly improved at both short-term and long-term final follow-up. There was no difference in PROs based on \\ atraumatic versus traumatic onset, or patients treated with a rotator interval closure. There was a significant difference in PROs between patients who had continued instability. Conclusion: APC for the treatment of MDI provided reasonable, durable long-term PROs that persisted from short-term follow-up. Although 29% of patients experienced feelings of instability at final follow-up, most of these patients still had high postoperative satisfaction and acceptable PROs.
Comparable Recovery and Compensatory Strategies in Heel-Rise Performance After a Surgically Repaired Acute Achilles Tendon Rupture: An In Vivo Kinematic Analysis Comparing Early Functional Mobilization and Standard Treatment
Authors: Aufwerber Susanna , Silbernagel Karin Grävare , Ackermann Paul W. , Naili Josefine E. 
Published: November 2022

Background: Deficits in calf muscle function and heel-rise performance are common after an Achilles tendon rupture (ATR) and are related to tendon elongation and calf muscle atrophy. Whether early functional mobilization (EFM) can improve calf muscle function compared with standard treatment (ST) with 2 weeks of immobilization and unloading in a plaster cast is unknown. Hypothesis: EFM would lead to superior recovery of heel-rise performance, as demonstrated by more symmetrical side-to-side ankle and knee joint kinematics, compared with ST. Study Design: Cohort study; Level of evidence, 2. Methods: In total, 47 patients with an ATR were prospectively included and treated with open surgical repair and randomized 2:1 postoperatively to either EFM or ST. Overall, 29 patients were treated with a dynamic orthosis (EFM), and 18 underwent ST. At 8 weeks and 6 months after ATR repair, 3-dimensional motion analysis of heel-rise performance was conducted. At 6 months, tendon length and muscle volume were assessed with ultrasound imaging, calf muscle function with the heel-rise test, and patient-reported outcomes with the Achilles tendon Total Rupture Score. Results: At 8 weeks and 6 months, there were no significant group differences between the EFM and ST groups in heel-rise performance, but significant side-to-side differences in ankle and knee kinematics were detected. At 8 weeks and 6 months, both the EFM and ST groups showed a significantly decreased peak ankle plantarflexion angle and increased knee flexion angle on the injured limb compared with the uninjured limb during bilateral heel raises. Linear regression demonstrated that greater atrophy of the medial gastrocnemius muscle ( P = .008) and higher body weight ( P < .001) were predictors of a decreased maximum peak ankle plantarflexion angle on the injured limb at 6 months. Conclusion: EFM after an ATR repair did not lead to superior recovery of calf muscle function, as assessed by heel-rise performance, compared with ST. Increased knee flexion seemed to be a compensatory strategy for decreased ankle plantarflexion. Medial gastrocnemius atrophy and increased body weight were additional factors associated with a decreased ankle plantarflexion angle. Registration: NCT02318472 (ClinicalTrials.gov identifier).
Predictive value of systemic immune-inflammation index in recurrent urethral strictures
Authors: Özsoy Emrah , Kutluhan Musab Ali , Tokuç Emre , Artuk İlker , Kayar Rıdvan , Akyüz Mehmet , Öztürk Metin İshak 
Published: November 2022

Purpose: To investigate the predictive value of systemic immune-inflammation index (SII) in recurrence of urethral stricture in patients undergoing internal urethrotomy Methods: In this two-center, retrospective study, 703 patients who had internal urethrotomy for urethral stricture were included. Demographic, clinical, and laboratory characteristics and operative data were obtained. Two groups were formed from the patients as non-recurrent urethral stricture ( n = 490) and recurrent urethral stricture ( n = 213). Results: There was no significant difference in the mean age between the patients with and without recurrence. There was a significant difference in the mean SII values and albumin levels between the recurrence and non-recurrence groups ( p = 0.001 and p = 0.006, respectively). Using a cut-off value of 252 for the SII; the sensitivity was 59.62%, the specificity was 70.41%, the positive predictive value was 46.69%, the negative predictive value was 80.05% and the accuracy was 67.14%, respectively. Statistically significant correlation was found between the presence of recurrence and the established cut-off value of the SII ( p = 0.001 and p < 0.01, respectively). The risk of recurrence was stated that 3.514 times higher in patients with a SII value of ⩾252. Conclusion: Using the SII the inflammatory state of the urethral tissue can be evaluated. Thus the risk of recurrence after internal urethrotomy operation can be predicted. Open urethroplasty technique instead of DVIU in patients with high SII values may increase the surgical success rates.
Outcomes of PD for AKI treatment during COVID-19 in New York City: A multicenter study
Authors: Sourial Maryanne Y , Gone Anirudh , Uribarri Jaime , Srivatana Vesh , Sharma Shuchita , Shimonov Daniil , Chang Michael , Mowrey Wenzhu , Dalsan Rochelle , Sedaliu Kaltrina , Jain Swati , Ross Michael J , Caplin Nina , Chen Wei ,   the New York City Peritoneal Dialysis Consortium
Published: November 2022

Background: The high incidence of acute kidney injury (AKI) requiring dialysis associated with COVID-19 led to the use of peritoneal dialysis (PD) for the treatment of AKI. This study aims to compare in-hospital all-cause mortality and kidney recovery between patients with AKI who received acute PD versus extracorporeal dialysis (intermittent haemodialysis and continuous kidney replacement therapy). Methods: In a retrospective observational study of 259 patients with AKI requiring dialysis during the COVID-19 surge during Spring 2020 in New York City, we compared 30-day all-cause mortality and kidney recovery between 93 patients who received acute PD at any time point and 166 patients who only received extracorporeal dialysis. Kaplan–Meier curves, log-rank test and Cox regression were used to compare survival and logistic regression was used to compare kidney recovery. Results: The mean age was 61 ± 11 years; 31% were women; 96% had confirmed COVID-19 with median follow-up of 21 days. After adjusting for demographics, comorbidities, oxygenation and laboratory values prior to starting dialysis, the use of PD was associated with a lower mortality rate compared to extracorporeal dialysis with a hazard ratio of 0.48 (95% confidence interval: 0.27–0.82, p = 0.008). At discharge or on day 30 of hospitalisation, there was no association between dialysis modality and kidney recovery ( p = 0.48). Conclusions: The use of PD for the treatment of AKI was not associated with worse clinical outcomes when compared to extracorporeal dialysis during the height of the COVID-19 pandemic in New York City. Given the inherent selection biases and residual confounding in our observational study, research with a larger cohort of patients in a more controlled setting is needed to confirm our findings.