bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development and validation of a genomic mutation signature to predict response to PD-1 inhibitors in non-squamous NSCLC: a multicohort study
Authors: Bai Xue , Wu De-Hua , Ma Si-Cong , Wang Jian , Tang Xin-Ran , Kang Shuai , Fu Qiang John , Cao Chuan-Hui , Luo He-San , Chen Yu-Han , Zhu Hong-Bo , Yan Hong-Hong , Wu Yi-Long , Dong Zhong-Yi 
Published: June 2020

BackgroundGenetic variations of some driver genes in non-small cell lung cancer (NSCLC) had shown potential impact on immune microenvironment and associated with response or resistance to programmed cell death protein 1 (PD-1) blockade immunotherapy. We therefore undertook an exploratory analysis to develop a genomic mutation signature (GMS) and predict the response to anti-PD-(L)1 therapy.MethodsIn this multicohort analysis, 316 patients with non-squamous NSCLC treated with anti-PD-(L)1 from three independent cohorts were included in our study. Tumor samples from the patients were molecularly profiled by MSK-IMPACT or whole exome sequencing. We developed a risk model named GMS based on the MSK training cohort (n=123). The predictive model was first validated in the separate internal MSK cohort (n=82) and then validated in an external cohort containing 111 patients from previously published clinical trials.ResultsA GMS risk model consisting of eight genes (TP53,KRAS,STK11,EGFR,PTPRD,KMT2C,SMAD4, andHGF) was generated to classify patients into high and low GMS groups in the training cohort. Patients with high GMS in the training cohort had longer progression-free survival (hazard ratio (HR) 0.41, 0.28–0.61, p<0.0001) and overall survival (HR 0.53, 0.32–0.89, p=0.0275) compared with low GMS. We noted equivalent findings in the internal validation cohort and in the external validation cohort. The GMS was demonstrated as an independent predictive factor for anti-PD-(L)1 therapy comparing with tumor mutational burden. Meanwhile, GMS showed undifferentiated predictive value in patients with different clinicopathological features. Notably, both GMS and PD-L1 were independent predictors and demonstrated poorly correlated; inclusion of PD-L1 with GMS further improved the predictive capacity for PD-1 blockade immunotherapy.ConclusionsOur study highlights the potential predictive value of GMS for immunotherapeutic benefit in non-squamous NSCLC. Besides, the combination of GMS and PD-L1 may serve as an optimal partner in guiding treatment decisions for anti-PD-(L)1 based therapy.
Transition to severe phenotype in systemic lupus erythematosus initially presenting with non-severe disease: implications for the management of early disease
Authors: Nikolopoulos Dionysis S , Kostopoulou Myrto , Pieta Antigoni , Flouda Sofia , Chavatza Katerina , Banos Aggelos , Boletis John , Katsimbri Pelagia , Boumpas Dimitrios T , Fanouriakis Antonis 
Published: June 2020

ObjectiveChanges in the care of patients with SLE dictate a re-evaluation of its natural history and risk factors for disease deterioration and damage accrual. We sought to decipher factors predictive of a deterioration in phenotype (‘transition’) in patients initially presenting with non-severe disease.MethodsPatients from the ‘Attikon’ cohort with disease duration ≥1 year were included. Disease at diagnosis was categorised as mild, moderate or severe, based on the British Isles Lupus Assessment Group manifestations and physician judgement. ‘Transition’ in severity was defined as an increase in category of severity at any time from diagnosis to last follow-up. Multivariable logistic regression was performed to identify baseline factors associated with this transition.Results462 patients were followed for a median (IQR) of 36 (120) months. At diagnosis, more than half (56.5%) had a mild phenotype. During disease course, transition to more severe forms was seen in 44.2%, resulting in comparable distribution among severity patterns at last follow-up (mild 28.4%, moderate 33.1%, severe 38.5%). Neuropsychiatric involvement at onset (OR 6.33, 95% CI 1.22 to 32.67), male sex (OR 4.53, 95% CI 1.23 to 16.60) and longer disease duration (OR 1.09 per 1 year, 95% CI 1.04 to 1.14) were independently associated with transition from mild or moderate to severe disease. Patients with disease duration ≥3 years who progressed to more severe disease had more than 20-fold increased risk to accrue irreversible damage.ConclusionAlmost half of patients with initially non-severe disease progress to more severe forms of SLE, especially men and patients with positive anti-double-stranded DNA or neuropsychiatric involvement at onset. These data may have implications for the management of milder forms of lupus.
Neuroendovascular clinical trials disruptions due to COVID-19. Potential future challenges and opportunities
Authors: Rai Ansaar T , Leslie-Mazwi Thabele M , Fargen Kyle M , Pandey Aditya S , Dabus Guilherme , Hassan Ameer E , Fraser Justin F , Hirsch Joshua A , Gupta Rishi , Hanel Ricardo , Yoo Albert J , Bozorgchami Hormozd , Fiorella David , Mocco J , Arthur Adam S , Zaidat Osama , Siddiqui Adnan H 
Published: June 2020

To assess the impact of COVID-19 on neurovascular research and deal with the challenges imposed by the pandemic.MethodsA survey-based study focused on randomized controlled trials (RCTs) and single-arm studies for acute ischemic stroke and cerebral aneurysms was developed by a group of senior neurointerventionalists and sent to sites identified through the clinical trials website (https://clinicaltrials.gov/), study sponsors, and physician investigators.ResultsThe survey was sent to 101 institutions, with 65 responding (64%). Stroke RCTs were being conducted at 40 (62%) sites, aneurysm RCTs at 22 (34%) sites, stroke single-arm studies at 37 (57%) sites, and aneurysm single-arm studies at 43 (66%) sites. Following COVID-19, enrollment was suspended at 51 (78%) sites—completely at 21 (32%) and partially at 30 (46%) sites. Missed trial-related clinics and imaging follow-ups and protocol deviations were reported by 27 (42%), 24 (37%), and 27 (42%) sites, respectively. Negative reimbursements were reported at 17 (26%) sites. The majority of sites, 49 (75%), had put new trials on hold. Of the coordinators, 41 (63%) worked from home and 20 (31%) reported a personal financial impact. Remote consent was possible for some studies at 34 (52%) sites and for all studies at 5 (8%) sites. At sites with suspended trials (n=51), endovascular treatment without enrollment occurred at 31 (61%) sites for stroke and 23 (45%) sites for aneurysms. A total of 277 patients with acute ischemic stroke and 184 with cerebral aneurysms were treated without consideration for trial enrollment.ConclusionWidespread disruption of neuroendovascular trials occurred because of COVID-19. As sites resume clinical research, steps to mitigate similar challenges in the future should be considered.
Regional geological analysis of the southern deep Gulf of Mexico and northern Yucatán Shelf
Authors: Miranda-Madrigal Ernesto , Chávez-Cabello Gabriel 
Published: June 2020

Abstract
We discuss the sedimentary and structural evolution, and oil possibilities, of a Late Jurassic-Early Cretaceous major salt detached extensional–contractional province in the Yucatán sub-basin at the southern Gulf of Mexico using 2D seismic reflection profiles and well data from the Deep Sea Drilling Project (DSDP). The main basement trends are a central depression that accommodates the pre-salt sequences, and a long ridge where the continental–oceanic crust transition is found. Along this ridge, the geometry of the outer trough was defined by mapping the base salt. The base salt changes from steeply dipping on the Campeche Escarpment to irregular-horizontal on the limit with the recognized outer trough. The extensional–contractional system was divided into three subdomains with: (1) tilted blocks; (2) growth faults and rollover anticlines; and (3) diapirs and fold and thrust. We regionally identify the highest sedimentation stages through the Tertiary, the possible main directions of sediment supply to the basin and their relationship to Neogene diapirism. The two structural traps formation times interpreted in the area are: (a) Late Jurassic-Early Cretaceous traps associated with seaward salt translation; and (b) middle Miocene–early Pliocene traps related to diapiric growth in the outer trough, triggered by sediment load derived from the north of the Gulf of Mexico and from SE Mexico, where the Chiapanecan Orogeny was developed. The integration of the results of this study with the evidence of some elements and processes of the petroleum system allow us to propose that the area may represent an important oil province.
Cancer-Associated Point Mutations in theDLC1Tumor Suppressor and OtherRho-GAPsOccur Frequently and Are Associated with Decreased Function
Authors: Wang Dunrui , Qian Xiaolan , Sanchez-Solana Beatriz , Tripathi Brajendra K. , Durkin Marian E. , Lowy Douglas R. 
Published: June 2020

AbstractIn advanced cancer, the RHOA GTPase is often active together with reduced expression of genes encoding Rho-specific GTPase-accelerating proteins (Rho-GAP), which negatively regulate RHOA and related GTPases. Here we used the The Cancer Genome Atlas dataset to examine 12 tumor types (including colon, breast, prostate, pancreas, lung adenocarcinoma, and squamous cell carcinoma) for the frequency of codon mutations of 10 Rho-GAP and experimentally tested biochemical and biological consequences for cancer-associated mutants that arose in the DLC1 tumor suppressor gene. DLC1 was the Rho-GAP gene mutated most frequently, with 5%–8% of tumors in five of the tumor types evaluated having DLC1 missense mutations. Furthermore, 20%–26% of the tumors in four of these five tumor types harbored missense mutations in at least one of the 10 Rho-GAPs. Experimental analysis of the DLC1 mutants indicated 7 of 9 mutants whose lesions were located in the Rho-GAP domain were deficient for Rho-GAP activity and for suppressing cell migration and anchorage-independent growth. Analysis of a DLC1 linker region mutant and a START domain mutant showed each was deficient for suppressing migration and growth in agar, but their Rho-GAP activity was similar to that of wild-type DLC1. Compared with the wild-type, the linker region mutant bound 14-3-3 proteins less efficiently, while the START domain mutant displayed reduced binding to Caveolin-1. Thus, mutation of Rho-GAP genes occurs frequently in some cancer types and the majority of cancer-associated DLC1 mutants evaluated were deficient biologically, with various mechanisms contributing to their reduced activity.Significance:These findings indicate that point mutation of Rho-GAP genes is unexpectedly frequent in several cancer types, with DLC1 mutants exhibiting reduced function by various mechanisms.
Palmitoylated Proteins on AML-Derived Extracellular Vesicles Promote Myeloid-Derived Suppressor Cell Differentiation via TLR2/Akt/mTOR Signaling
Authors: Tohumeken Sehmus , Baur Rebecca , Böttcher Martin , Stoll Andrej , Loschinski Romy , Panagiotidis Konstantinos , Braun Martina , Saul Domenica , Völkl Simon , Baur Andreas S. , Bruns Heiko , Mackensen Andreas , Jitschin Regina , Mougiakakos Dimitrios 
Published: June 2020

Abstract

Acute myeloid leukemia (AML) represents the most common acute leukemia among adults. Despite recent progress in diagnosis and treatment, long-term outcome remains unsatisfactory. The success of allogeneic stem cell transplantation underscores the immunoresponsive nature of AML, creating the basis for further exploiting immunotherapies. However, emerging evidence suggests that AML, similar to other malignant entities, employs a variety of mechanisms to evade immunosurveillance. In light of this, T-cell inhibitory myeloid-derived suppressor cells (MDSC) are gaining interest as key facilitators of immunoescape. Accumulation of CD14+HLA-DRlow monocytic MDSCs has been described in newly diagnosed AML patients, and deciphering the underlying mechanisms could help to improve anti-AML immunity. Here, we report that conventional monocytes readily take-up AML-derived extracellular vesicles (EV) and subsequently undergo MDSC differentiation. They acquired an CD14+HLA-DRlow phenotype, expressed the immunomodulatory indoleamine-2,3-dioxygenase, and upregulated expression of genes characteristic for MDSCs, such as S100A8/9 and cEBPβ. The Akt/mTOR pathway played a critical role in the AML-EV–induced phenotypical and functional transition of monocytes. Generated MDSCs displayed a glycolytic switch, which rendered them more susceptible toward glycolytic inhibitors. Furthermore, palmitoylated proteins on the AML-EV surface activated Toll-like receptor 2 as the initiating event of Akt/mTOR-dependent induction of MDSC. Therefore, targeting protein palmitoylation in AML blasts could block MDSC accumulation to improve immune responses.

Significance:
These findings indicate that targeting protein palmitoylation in AML could interfere with the leukemogenic potential and block MDSC accumulation to improve immunity.
Chemerin Reactivates PTEN and Suppresses PD-L1 in Tumor Cells via Modulation of a Novel CMKLR1-mediated Signaling Cascade
Authors: Rennier Keith , Shin Woo Jae , Krug Ethan , Virdi Gurpal , Pachynski Russell K. 
Published: June 2020

Abstract

Purpose:
Chemerin (retinoic acid receptor responder 2, RARRES2) is an endogenous leukocyte chemoattractant that recruits innate immune cells through its receptor, ChemR23. RARRES2 is widely expressed in nonhematopoietic tissues and often downregulated across multiple tumor types compared with normal tissue. Recent studies show that augmenting chemerin in the tumor microenvironment significantly suppresses tumor growth, in part, by immune effector cells recruitment. However, as tumor cells express functional chemokine/chemoattractant receptors that impact their phenotype, we hypothesized that chemerin may have additional, tumor-intrinsic effects.

Experimental Design:
We investigated the effect of exogenous chemerin on human prostate and sarcoma tumor lines. Key signaling pathway components were elucidated using qPCR, Western blotting, siRNA knockdown, and specific inhibitors. Functional consequences of chemerin treatment were evaluated using in vitro and in vivo studies.

Results:
We show for the first time that human tumors exposed to exogenous chemerin significantly upregulate PTEN expression/activity, and concomitantly suppress programmed death ligand-1 (PD-L1) expression. CMKLR1 knockdown abrogated chemerin-induced PTEN and PD-L1 modulation, exposing a novel CMKLR1/PTEN/PD-L1 signaling cascade. Targeted inhibitors suggested signaling was occurring through the PI3K/AKT/mTOR pathway. Chemerin treatment significantly reduced tumor migration, while significantly increasing T-cell–mediated cytotoxicity. Chemerin treatment was as effective as both PD-L1 knockdown and the anti–PD-L1 antibody, atezolizumab, in augmenting T-cell–mediated tumor lysis. Forced expression of chemerin in human DU145 tumors significantly suppressed in vivo tumor growth, and significantly increased PTEN and decreased PD-L1 expression.

Conclusions:
Collectively, our data show a novel link between chemerin, PTEN, and PD-L1 in human tumor lines, which may have a role in improving T-cell–mediated immunotherapies.
Comparison of Panitumumab-IRDye800CW and 5-Aminolevulinic Acid to Provide Optical Contrast in a Model of Glioblastoma Multiforme
Authors: Napier Tiara S. , Udayakumar Neha , Jani Aditi H. , Hartman Yolanda E. , Houson Hailey A. , Moore Lindsay , Amm Hope M. , van den Berg Nynke S. , Sorace Anna G. , Warram Jason M. 
Published: June 2020

Abstract
Maximal safe resection of malignant tissue is associated with improved progression-free survival and better response to radiation and chemotherapy for patients with glioblastoma (GBM). 5-Aminolevulinic acid (5-ALA) is the current FDA-approved standard for intraoperative brain tumor visualization. Unfortunately, autofluorescence in diffuse areas and high fluorescence in dense tissues significantly limit discrimination at tumor margins. This study is the first to compare 5-ALA to an investigational new drug, panitumumab-IRDye800CW, in the same animal model. A patient-derived GBM xenograft model was established in 16 nude mice, which later received injections of 5-ALA, panitumumab-IRDye800CW, IRDye800CW, 5-ALA and IRDye800CW, or 5-ALA and panitumumab-IRDye800CW. Brains were prepared for multi-instrument fluorescence imaging, IHC, and quantitative analysis of tumor-to-background ratio (TBR) and tumor margin accuracy. Statistical analysis was compared with Wilcoxon rank-sum or paired t test. Panitumumab-IRDye800CW had a 30% higher comprehensive TBR compared with 5-ALA (P = 0.0079). SDs for core and margin regions of interest in 5-ALA–treated tissues were significantly higher than those found in panitumumab-IRDye800CW–treated tissues (P = 0.0240 and P = 0.0284, respectively). Panitumumab-IRDye800CW specificities for tumor core and margin were more than 10% higher than those of 5-ALA. Higher AUC for panitumumab-IRDye800CW indicated strong capability to discriminate between normal and malignant brain tissue when compared with 5-ALA. This work demonstrates that panitumumab-IRDye800CW shows potential as a targeting agent for fluorescence intraoperative detection of GBM. Improved margin definition and surgical resection using panitumumab-IRDye800 has the potential to improve surgical outcomes and survival in patients with GBM compared with 5-ALA.
Allosteric Inhibition of ABL Kinases: Therapeutic Potential in Cancer
Authors: Jones Jill K. , Thompson Eric M. 
Published: June 2020

Abstract
Tyrosine kinase inhibitors have revolutionized the world of cancer treatment in recent years, profoundly improving survival of patients with chronic myeloid leukemia (CML) and beyond. However, off-target toxicities of these inhibitors are well-described, and resistance has become a paramount concern. Novel allosteric inhibitors of the Abelson (ABL) family of tyrosine kinases, including GNF-2, GNF-5, and ABL-001, are equipped to overcome these issues. Several contemporary studies have demonstrated their potential efficacy in three key areas: primary hematologic and solid malignancies, metastasis, and combination with other small molecules. Further, ongoing clinical trials are investigating the efficacy of ABL-001 for the treatment of CML and recurrent solid tumors. This work reviews the current literature of the preclinical testing of GNF-2 and GNF-5 and the preclinical and clinical testing of ABL-001. Future research will continue to evaluate these promising inhibitors as both first-line therapy for solid tumors and salvage therapy when more traditional drugs such as imatinib fail.
Poly(ADP-ribose) Glycohydrolase Inhibition Sequesters NAD+ to Potentiate the Metabolic Lethality of Alkylating Chemotherapy in IDH-Mutant Tumor Cells
Authors: Nagashima Hiroaki , Lee Christine K. , Tateishi Kensuke , Higuchi Fumi , Subramanian Megha , Rafferty Seamus , Melamed Lisa , Miller Julie J. , Wakimoto Hiroaki , Cahill Daniel P. 
Published: June 2020

Abstract

NAD+ is an essential cofactor metabolite and is the currency of metabolic transactions critical for cell survival. Depending on tissue context and genotype, cancer cells have unique dependencies on NAD+ metabolic pathways. PARPs catalyze oligomerization of NAD+ monomers into PAR chains during cellular response to alkylating chemotherapeutics, including procarbazine or temozolomide. Here we find that, in endogenous IDH1-mutant tumor models, alkylator-induced cytotoxicity is markedly augmented by pharmacologic inhibition or genetic knockout of the PAR breakdown enzyme PAR glycohydrolase (PARG). Both in vitro and in vivo, we observe that concurrent alkylator and PARG inhibition depletes freely available NAD+ by preventing PAR breakdown, resulting in NAD+ sequestration and collapse of metabolic homeostasis. This effect reversed with NAD+ rescue supplementation, confirming the mechanistic basis of cytotoxicity. Thus, alkylating chemotherapy exposes a genotype-specific metabolic weakness in tumor cells that can be exploited by PARG inactivation.

Significance:
Oncogenic mutations in the isocitrate dehydrogenase genes IDH1 or IDH2 initiate diffuse gliomas of younger adulthood. Strategies to maximize the effectiveness of chemotherapy in these tumors are needed. We discover alkylating chemotherapy and concurrent PARG inhibition exploits an intrinsic metabolic weakness within these cancer cells to provide genotype-specific benefit.
See related commentary by Pirozzi and Yan, p. 1629.
This article is highlighted in the In This Issue feature, p. 1611
The Use of Lasers in Stapes Surgery
Authors: Srivastava Rishi , Cho Waisum , Fergie Neil 
Published: June 2020

Objectives: Otosclerosis is a disease process that usually starts around the oval window, causing fixation of the stapes, resulting in conductive hearing loss. Treatment of the conductive hearing loss caused by otosclerosis consists of either rehabilitation with hearing aids or performing surgery. Given the risks of hearing impairment and vertigo associated with the surgery, there has been a desire to advance the practice to minimize the complications. The so-called “non-contact” or “no touch” techniques with the use of various lasers are in current practice. This review article will cover the surgical aspects, the theory behind laser and the various types used in stapes surgery. It will also review the evidence of laser versus conventional stapes surgery and the comparison of different laser types. Methods: A literature search up to December 2019 was performed using Pubmed and a nonsystematic review of appropriate articles was undertaken. Keywords used were stapes, surgery, laser, stapedectomy, and stapedotomy. Results: Overall, there is no evidence to say laser fenestration is better than conventional fenestration techniques; however, with the micro drill, there is an increased risk of footplate fracture and sensorineural hearing loss. There is an increased risk of tinnitus with the laser compared to conventional techniques. Studies have favored the CO2 laser over potassium titanyl phosphate (KTP) and erbium-doped yttrium aluminium garnet (Erbium-YAG) lasers for postoperative closure of the air-bone gap; and KTP laser has less thermal, mechanical, and sound effects compared with the thulium and carbon dioxide (CO2) lasers. There is an increased risk if inner ear complications with the thulium laser. Conclusions: It can be deduced that theoretically and practically, the thulium laser is less safe compared to the KTP and CO2 lasers. The choice of laser used depends on the surgeon’s preference, as well as availability, cost, side effects profile, as well as ease of use.