bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multifactorial Deep Learning Reveals Pan-Cancer Genomic Tumor Clusters with Distinct Immunogenomic Landscape and Response to Immunotherapy
Authors: Xie Feng , Zhang Jianjun , Wang Jiayin , Reuben Alexandre , Xu Wei , Yi Xin , Varn Frederick S. , Ye Yongsheng , Cheng Junwen , Yu Miao , Wang Yue , Liu Yufeng , Xie Mingchao , Du Peng , Ma Ke , Ma Xin , Zhou Penghui , Yang Shengli , Chen Yaobing , Wang Guoping , Xia Xuefeng , Liao Zhongxing , Heymach John V. , Wistuba Ignacio I. , Futreal P. Andrew , Ye Kai , Cheng Chao , Xia Tian 
Published: January 2020

Abstract

Purpose:
Tumor genomic features have been of particular interest because of their potential impact on the tumor immune microenvironment and response to immunotherapy. Due to the substantial heterogeneity, an integrative approach incorporating diverse molecular features is needed to characterize immunologic features underlying primary resistance to immunotherapy and for the establishment of novel predictive biomarkers.

Experimental Design:
We developed a pan-cancer deep machine learning model integrating tumor mutation burden, microsatellite instability, and somatic copy-number alterations to classify tumors of different types into different genomic clusters, and assessed the immune microenvironment in each genomic cluster and the association of each genomic cluster with response to immunotherapy.

Results:
Our model grouped 8,646 tumors of 29 cancer types from The Cancer Genome Atlas into four genomic clusters. Analysis of RNA-sequencing data revealed distinct immune microenvironment in tumors of each genomic class. Furthermore, applying this model to tumors from two melanoma immunotherapy clinical cohorts demonstrated that patients with melanoma of different genomic classes achieved different benefit from immunotherapy. Interestingly, tumors in cluster 4 demonstrated a cold immune microenvironment and lack of benefit from immunotherapy despite high microsatellite instability burden.

Conclusions:
Our study provides a proof for principle that deep learning modeling may have the potential to discover intrinsic statistical cross-modality correlations of multifactorial input data to dissect the molecular mechanisms underlying primary resistance to immunotherapy, which likely involves multiple factors from both the tumor and host at different molecular levels.
Characterization of Immune Dysfunction and Identification of Prognostic Immune-Related Risk Factors in Acute Myeloid Leukemia
Authors: Tang Lu , Wu Jianghua , Li Cheng-Gong , Jiang Hui-Wen , Xu Min , Du Mengyi , Yin Zhinan , Mei Heng , Hu Yu 
Published: January 2020

Abstract

Purpose:
This study aims to provide comprehensive insights into longitudinal immune landscape in acute myeloid leukemia (AML) development and treatment, which may contribute to predict prognosis and guide clinical decisions.

Experimental Design:
Periphery blood samples from 79 patients with AML (at diagnosis or/and after chemotherapy or at relapse) and 24 healthy controls were prospectively collected. We performed phenotypic and functional analysis of various lymphocytes through multiparametric flow cytometry and investigated prognostic immune-related risk factors.

Results:
Immune defects in AML were reflected in T and natural killer (NK) cells, whereas B-cell function remained unaffected. Both CD8+ T and CD4+ T cells exhibited features of senescence and exhaustion at diagnosis. NK dysfunction was supported by excessive maturation and downregulation of NKG2D and NKP30. Diseased γδ T cells demonstrated a highly activated or even exhausted state through PD-1 upregulation and NKG2D downregulation. Effective therapeutic response following chemotherapy correlated with T and NK function restoration. Refractory and relapsed patients demonstrated even worse immune impairments, and selective immune signatures apparently correlated clinical outcomes and survival. PD-1 expression in CD8+ T cells was independently predictive of poor overall survival and event-free survival.

Conclusions:
T-cell senescence and exhaustion, together with impaired NK and γδ T-cell function, are dominant aspects involved in immune dysfunction in AML. Noninvasive immune testing of blood samples could be applied to predict therapeutic reactivity, high risk for relapse, and unfavorable prognosis.
Efficacy of FGFR Inhibitors and Combination Therapies for Acquired Resistance in FGFR2-Fusion Cholangiocarcinoma
Authors: Krook Melanie A. , Lenyo Alexandria , Wilberding Max , Barker Hannah , Dantuono Mikayla , Bailey Kelly M. , Chen Hui-Zi , Reeser Julie W. , Wing Michele R. , Miya Jharna , Samorodnitsky Eric , Smith Amy M. , Dao Thuy , Martin Dorrelyn M. , Ciombor Kristen K. , Hays John , Freud Aharon G. , Roychowdhury Sameek 
Published: January 2020

AbstractThe fibroblast growth factor receptor (FGFR) signaling pathway is aberrantly activated in approximately 15% to 20% of patients with intrahepatic cholangiocarcinoma. Currently, several FGFR kinase inhibitors are being assessed in clinical trials for patients with FGFR-altered cholangiocarcinoma. Despite evidence of initial responses and disease control, virtually all patients eventually develop acquired resistance. Thus, there is a critical need for the development of innovative therapeutic strategies to overcome acquired drug resistance. Here, we present findings from a patient with FGFR2-altered metastatic cholangiocarcinoma who enrolled in a phase II clinical trial of the FGFR inhibitor, infigratinib (BGJ398). Treatment was initially effective as demonstrated by imaging and tumor marker response; however, after 8 months on trial, the patient exhibited tumor regrowth and disease progression. Targeted sequencing of tumor DNA after disease progression revealed the FGFR2 kinase domain p.E565A and p.L617M single-nucleotide variants (SNV) hypothesized to drive acquired resistance to infigratinib. The sensitivities of these FGFR2 SNVs, which were detected post-infigratinib therapy, were extended to include clinically relevant FGFR inhibitors, including AZD4547, erdafitinib (JNJ-42756493), dovitinib, ponatinib, and TAS120, and were evaluated in vitro. Through a proteomics approach, we identified upregulation of the PI3K/AKT/mTOR signaling pathway in cells harboring the FGFR2 p.E565A mutation and demonstrated that combination therapy strategies with FGFR and mTOR inhibitors may be used to overcome resistance to FGFR inhibition, specific to infigratinib. Collectively, these studies support the development of novel combination therapeutic strategies in addition to the next generation of FGFR inhibitors to overcome acquired resistance in patients.
Immunoadsorption for Recurrent Primary Focal Segmental Glomerulosclerosis on Kidney Allografts: A Single-Center Experience and Literature Review
Authors: Naciri Bennani Hamza , Bonzi Juste Yérémandé , Noble Johan , Terrec Florian , Motte Lionel , Imerzoukene Farida , Bugnazet Mathilde , Giovannini Diane , Janbon Bénédicte , Malvezzi Paolo , Rostaing Lionel , Jouve Thomas 
Published: January 2020

<b><i>Introduction:</i></b> Primary focal and segmental glomerulosclerosis (FSGS) frequently reoccurs on kidney transplants and may lead to premature allograft loss. There are no guidelines for treating FSGS recurrence on allografts; treatment is based on apheresis (plasma exchange plasmapheresis [PP], semi-specific immunoadsorption [IA] with reusable columns) plus rituximab. <b><i>Objective:</i></b> We aimed to assess the efficacy of IA to treat recurrent FSGS. <b><i>Methods:</i></b> We report on 7 patients with recurrent FSGS on kidney allograft (proteinuria ≥3 g/g of urinary creatinine or ≥3 g/day); they all received IA. Our primary objective was to reduce proteinuria by &#x3e;50%. Patients’ mean age was 45 ± 10 years. Postoperative immunosuppression relied on steroids, mycophenolate mofetil, tacrolimus, with an induction therapy of basiliximab or antithymocyte globulins. Prophylaxis to prevent FSGS recurrence was either rituximab alone (<i>n</i> = 3), rituximab plus either PP or IA (<i>n</i> = 3), or no treatment (<i>n</i> = 1). Mean follow-up was 20 ± 13 months. There was a median of 72 (14–101) IA sessions per patient, that is, a mean of 14 ± 1 sessions per IA column. <b><i>Results:</i></b> At 12 months after starting IA, all patients had partial (<i>n</i> = 6) or complete (<i>n</i> = 1) remission, and allograft survival was 100%. The mean reduction in proteinuria within an IA session was 45 ± 15%. At last follow-up, 2 patients are in remission without IA, 3 patients are in partial remission that is IA dependent, and 2 patients lost their allograft due to FSGS recurrence. The most frequent adverse event was cytomegalovirus reactivation (<i>n</i> = 13), which subsided after valganciclovir therapy. <b><i>Conclusions:</i></b> We show that recurrence of FSGS can be controlled long term with IA plus rituximab. However, some patients remained dependent on IA.
Liver Fibrosis Indices and Outcomes After Primary Intracerebral Hemorrhage
Authors: Parikh Neal S. , Kamel Hooman , Navi Babak B. , Iadecola Costantino , Merkler Alexander E. , Jesudian Arun , Dawson Jesse , Falcone Guido J. , Sheth Kevin N. , Roh David J. , Elkind Mitchell S.V. , Hanley Daniel F. , Ziai Wendy C. , Murthy Santosh B. , Hanley Daniel F. , Butcher Kenneth , Davis Stephen M. , Gregson Barbara , Lees Kennedy R. , Lyden Patrick D. , Mayer Stephan A. , Muir Keith , Steiner Thorsten 
Published: January 2020

Background and Purpose—
Cirrhosis—clinically overt, advanced liver disease—is associated with an increased risk of hemorrhagic stroke and poor stroke outcomes. We sought to investigate whether subclinical liver disease, specifically liver fibrosis, is associated with clinical and radiological outcomes in patients with primary intracerebral hemorrhage.

Methods—
We performed a retrospective cohort study using data from the Virtual International Stroke Trials Archive–Intracerebral Hemorrhage. We included adult patients with primary intracerebral hemorrhage presenting within 6 hours of symptom onset. We calculated 3 validated fibrosis indices—Aspartate Aminotransferase–Platelet Ratio Index, Fibrosis-4 score, and Nonalcoholic Fatty Liver Disease Fibrosis Score—and modeled them as continuous exposure variables. Primary outcomes were admission hematoma volume and hematoma expansion. Secondary outcomes were mortality, and the composite of major disability or death, at 90 days. We used linear and logistic regression models adjusted for previously established risk factors.

Results—
Among 432 patients with intracerebral hemorrhage, the mean Aspartate Aminotransferase–Platelet Ratio Index, Fibrosis-4, and Nonalcoholic Fatty Liver Disease Fibrosis Score values on admission reflected intermediate probabilities of fibrosis, whereas standard hepatic assays and coagulation parameters were largely normal. After adjusting for potential confounders, Aspartate Aminotransferase–Platelet Ratio Index was associated with hematoma volume (β, 0.20 [95% CI, 0.04–0.36]), hematoma expansion (odds ratio, 1.6 [95% CI, 1.1–2.3]), and mortality (odds ratio, 1.8 [95% CI, 1.1–2.7]). Fibrosis-4 was also associated with hematoma volume (β, 0.27 [95% CI, 0.07–0.47]), hematoma expansion (odds ratio, 1.9 [95% CI, 1.2–3.0]), and mortality (odds ratio, 2.0 [95% CI, 1.1–3.6]). Nonalcoholic Fatty Liver Disease Fibrosis Score was not associated with any outcome. Indices were not associated with the composite of major disability or death.

Conclusions—
In patients with largely normal liver chemistries, 2 liver fibrosis indices were associated with admission hematoma volume, hematoma expansion, and mortality after intracerebral hemorrhage.
Why Are Stratospheric Sudden Warmings Sudden (and Intermittent)?
Authors: Nakamura Noboru , Falk Jonathan , Lubis Sandro W. 
Published: January 2020

Abstract
This paper examines the role of wave–mean flow interaction in the onset and suddenness of stratospheric sudden warmings (SSWs). Evidence is presented that SSWs are, on average, a threshold behavior of finite-amplitude Rossby waves arising from the competition between an increasing wave activity A and a decreasing zonal-mean zonal wind u¯. The competition puts a limit to the wave activity flux that a stationary Rossby wave can transmit upward. A rapid, spontaneous vortex breakdown occurs once the upwelling wave activity flux reaches the limit, or equivalently, once u¯ drops below a certain fraction of uREF, a wave-free, reference-state wind inverted from the zonalized quasigeostrophic potential vorticity. This fraction is 0.5 in theory and about 0.3 in reanalyses. We propose r≡u¯/uREF as a local, instantaneous measure of the proximity to vortex breakdown (i.e., preconditioning). The ratio r generally stays above the threshold during strong-vortex winters until a pronounced final warming, whereas during weak-vortex winters it approaches the threshold early in the season, culminating in a precipitous drop in midwinter as SSWs form. The essence of the threshold behavior is captured by a semiempirical 1D model of SSWs, similar to the “traffic jam” model of Nakamura and Huang for atmospheric blocking. This model predicts salient features of SSWs including rapid vortex breakdown and downward migration of the wave activity/zonal wind anomalies, with analytical expressions for the respective time scales. The model’s response to a variety of transient wave forcing and damping is discussed.
Climatology and Interannual Variability of Floods during the TRMM Era (1998–2013)
Authors: Yan Yan , Wu Huan , Gu Guojun , Huang Zhijun , Alfieri Lorenzo , Li Xiaomeng , Nanding Nergui , Pan Xinshun , Tang Qiuhong 
Published: January 2020

AbstractSpatial and temporal variations of global floods during the TRMM period (1998–2013) are explored by means of the outputs of the Dominant River Routing Integrated with VIC Environment model (DRIVE) driven by the precipitation rates from the TRMM Multisatellite Precipitation Analysis (TMPA). Climatological and seasonal mean features of floods including frequency (FF), duration (FD), and mean and total intensity (FI and FTI) are examined and further compared to those for a variety of precipitation indices derived from the daily TMPA rain rates. In general, floods and precipitation manifest similar spatial distributions, confirming that more precipitation (both amount and frequency) often indicates higher probability of floods. However, different flood indices can be associated with different precipitation characteristics with a highly region-dependent distribution. FF and FD tend to be more related to daily precipitation frequency globally, especially the mid- to high-end precipitation frequencies (F10, F25, F50). However, FI and FTI tend to be more associated with the mean volume/magnitude of those (extreme) daily precipitation events (Pr10 and Pr25). Nonetheless, daily precipitation intensity except the very high end one (R50) generally has a relatively weak effect on floods. The precipitation–flood relations at the 10 large regions are further examined, providing an improved understanding of precipitation-related flood-generating mechanisms in different locations. On the interannual time scale, El Niño–Southern Oscillation (ENSO) can significantly affect floods in many flood-prone zones. However, it is noted that even though the ENSO effect on floods is mostly through modulating various aspects of precipitation events, significant ENSO signals in precipitation cannot always translate to an effective, simultaneous impact on floods.
Oceanic Impacts on MJOs Detouring near the Maritime Continent
Authors: Zhou Lei , Murtugudde Raghu 
Published: January 2020

AbstractMadden–Julian oscillations (MJOs) are the dominant mode of intraseasonal variability (ISV) in the atmosphere acting as a bridge between weather and climate. During boreal winter, many MJO events are detoured southward while propagating across the Maritime Continent. Although MJO simulations have been greatly improved in recent years, the mechanism and simulation of MJO detouring near the Maritime Continent are still a great scientific challenge. Several mechanisms have been proposed based on atmospheric dynamics and thermodynamics. In this study, the oceanic role in MJO detouring is diagnosed using observations and reanalysis products. It is found that warm sea surface temperature (SST) anomalies occur over the southeastern Indian Ocean that induce a cyclone in the lower troposphere. Due to the westerly background winds, westerly winds are strengthened (weakened) to the north (south) of warm SST anomalies. As a result, the latent heat flux (LHF) is enhanced, and convection is reinforced to the north of warm SST anomalies. In contrast, the LHF is reduced, and SSTs warm to the south of pre-existing warm SST anomalies. Hence, the warm SST anomalies and convection system shift the MJOs southward before they reach the Maritime Continent. The identification of the oceanic influence on the MJO detouring deepens our understanding of the mechanism of their detour and elicits the role of the ocean. It is expected to brighten the prospects for better simulation and forecast of MJOs over the Maritime Continent. The oceanic ISV in the southeastern Indian Ocean is subject to many forcings, such as intraseasonal atmospheric forcing, the Indonesian Throughflow, local oceanic instability, and coastal Kelvin waves along Sumatra. Determining the mechanism of ISV in the southeastern Indian Ocean requires further dedicated studies.
Corridors of Mei-Yu-Season Rainfall over Eastern China
Authors: Guan Peiying , Chen Guixing , Zeng Wenxin , Liu Qian 
Published: January 2020

AbstractSuccessive mesoscale convective systems may develop for several days during the mei-yu season (June–July) over eastern China. They can yield excessive rainfall in a narrow latitudinal band (called a corridor), causing severe floods. The climatology of rainfall corridors and related environmental factors are examined using 20 yr of satellite rainfall and atmospheric data. A total of 93 corridors are observed over eastern China, with maximum occurrence at 27°–31°N. They typically last 2–3 days, but some persist ≥4 days, with an extreme event lasting 11 days. These multiday convective episodes exhibit primary and secondary peaks in the morning and afternoon, respectively, with a diurnal cycle that is in contrast to other afternoon-peak rain events. On average, the corridors occur in ~23% days of the mei-yu season, but they can contribute ~51% of the total rainfall. They also vary with years and explain ~70% of the interannual variance of mei-yu-season rainfall. Composite analyses show that most corridors develop along zonally oriented quasi-stationary mei-yu fronts over central China where monsoon southwesterlies converge with northerly anomalies from the midlatitudes. The monsoon flow accelerates at ~0200 LST and forms a regional wind maximum or low-level jet over South China, which induces moisture flux convergence in morning-peak corridors. The nocturnal acceleration is less evident for afternoon-peak corridors. The mei-yu front and monsoon southwesterlies also influence the corridor’s duration, which is regulated by a dipole of geopotential anomalies, with positive in the tropics and negative in the midlatitudes. The dipole expresses a joint influence of the blocking patterns in midlatitudes and the El Niño–related anomalous high over the western Pacific Ocean, and the dipole's intensity explains well the interannual variations of the corridors.
Mooring Observations of Air–Sea Heat Fluxes in Two Subantarctic Mode Water Formation Regions
Authors: Tamsitt Veronica , Cerovečki Ivana , Josey Simon A. , Gille Sarah T. , Schulz Eric 
Published: January 2020

AbstractWintertime surface ocean heat loss is the key process driving the formation of Subantarctic Mode Water (SAMW), but there are few direct observations of heat fluxes, particularly during winter. The Ocean Observatories Initiative (OOI) Southern Ocean mooring in the southeast Pacific Ocean and the Southern Ocean Flux Station (SOFS) in the southeast Indian Ocean provide the first concurrent, multiyear time series of air–sea fluxes in the Southern Ocean from two key SAMW formation regions. In this work we compare drivers of wintertime heat loss and SAMW formation by comparing air–sea fluxes and mixed layers at these two mooring locations. A gridded Argo product and the ERA5 reanalysis product provide temporal and spatial context for the mooring observations. Turbulent ocean heat loss is on average 1.5 times larger in the southeast Indian (SOFS) than in the southeast Pacific (OOI), with stronger extreme heat flux events in the southeast Indian leading to larger cumulative winter ocean heat loss. Turbulent heat loss events in the southeast Indian (SOFS) occur in two atmospheric regimes (cold air from the south or dry air circulating via the north), while heat loss events in the southeast Pacific (OOI) occur in a single atmospheric regime (cold air from the south). On interannual time scales, wintertime anomalies in net heat flux and mixed layer depth (MLD) are often correlated at the two sites, particularly when wintertime MLDs are anomalously deep. This relationship is part of a larger basin-scale zonal dipole in heat flux and MLD anomalies present in both the Indian and Pacific basins, associated with anomalous meridional atmospheric circulation.
The Hybrid-Scan Estimators: Exploiting WSR-88D Split Cuts to Improve the Quality of Polarimetric-Variable Estimates
Authors: Schvartzman David , Torres Sebastián M. , Warde David 
Published: January 2020

AbstractSince the dual-polarization upgrade of the Weather Surveillance Radar-1988 Doppler (WSR-88D), the polarimetric variables have become a fundamental tool for better interpretation and forecasting of hazardous weather events. Thus, improving their quality has been an important long-standing effort. In this paper, we introduce the hybrid-scan estimators (HSE), which use the available data in split cuts of operational volume coverage patterns (VCP) to provide better estimates of differential reflectivity, differential phase, and correlation coefficient. The HSE are designed to choose between the data provided by either one of the two scans in split cuts based on their expected statistical performance, resulting in the same or better data quality compared to the conventional estimators. The performance improvement realized with the HSE is characterized with simulations and illustrated with data from WSR-88D. While relatively simple, an operational implementation of the HSE could bring improvements to forecasters’ data interpretation and algorithm performance, both of which rely on dual-polarization radar data.
Botulinum Toxin for the Treatment of Motor and Phonic Tics: A Case Report
Authors: Kohli Nikita , Blitzer Andrew 
Published: January 2020

Objective: To present a unique approach to the treatment of motor and phonic tics. Patient: A 26-year-old male presented with motor and phonic tics including grunting, coughing, and throat clearing. Intervention: The patient was treated with 2.5 units of onabotulinum toxin A (BoNT) to the facial mimetic musculature and 2.5 units to each supraglottic musculature via a transthyrohyoid membrane approach under fiberoptic visualization. Results: The patient experienced reduction in the frequency, intensity, and interference with daily life of motor and phonic tics on the Yale Global Tic Severity Scale (YGTSS). Conclusion: This patient experienced subjective and objective decreases in tic severity using a unique approach in the treatment of phonic tics. Results suggest a novel approach in the treatment of phonic tics and bolster the data regarding safe and effective use of BoNT for tic disorder. Level of evidence: Level V, case report.