bluuebunny/crossref_metadata_2025_split huggingface dataset:
Angiopoietin-2–Dependent Spatial Vascular Destabilization Promotes T-cell Exclusion and Limits Immunotherapy in Melanoma
Authors: Park Ha-Ram , Shiva Anahita , Cummings Portia , Kim Seoyeon , Kim Sungsoo , Lee Eunhyeong , Leong Alessandra , Chowdhury Subrata , Shawber Carrie , Carvajal Richard , Thurston Gavin , An Joon-Yong , Lund Amanda W. , Yang Hee Won , Kim Minah 
Published: April 2023

Abstract

T-cell position in the tumor microenvironment determines the probability of target encounter and tumor killing. CD8+ T-cell exclusion from the tumor parenchyma is associated with poor response to immunotherapy, and yet the biology that underpins this distinct pattern remains unclear. Here we show that the vascular destabilizing factor angiopoietin-2 (ANGPT2) causes compromised vascular integrity in the tumor periphery, leading to impaired T-cell infiltration to the tumor core. The spatial regulation of ANGPT2 in whole tumor cross-sections was analyzed in conjunction with T-cell distribution, vascular integrity, and response to immunotherapy in syngeneic murine melanoma models. T-cell exclusion was associated with ANGPT2 upregulation and elevated vascular leakage at the periphery of human and murine melanomas. Both pharmacologic and genetic blockade of ANGPT2 promoted CD8+ T-cell infiltration into the tumor core, exerting antitumor effects. Importantly, the reversal of T-cell exclusion following ANGPT2 blockade not only enhanced response to anti-PD-1 immune checkpoint blockade therapy in immunogenic, therapy-responsive mouse melanomas, but it also rendered nonresponsive tumors susceptible to immunotherapy. Therapeutic response after ANGPT2 blockade, driven by improved CD8+ T-cell infiltration to the tumor core, coincided with spatial TIE2 signaling activation and increased vascular integrity at the tumor periphery where endothelial expression of adhesion molecules was reduced. These data highlight ANGPT2/TIE2 signaling as a key mediator of T-cell exclusion and a promising target to potentiate immune checkpoint blockade efficacy in melanoma.

Significance:
ANGPT2 limits the efficacy of immunotherapy by inducing vascular destabilization at the tumor periphery to promote T-cell exclusion.
Tackling Osimertinib Resistance in EGFR-Mutant Non–Small Cell Lung Cancer
Authors: Blaquier Juan Bautista , Ortiz-Cuaran Sandra , Ricciuti Biagio , Mezquita Laura , Cardona Andrés Felipe , Recondo Gonzalo 
Published: April 2023

AbstractThe current landscape of targeted therapies directed against oncogenic driver alterations in non–small cell lung cancer (NSCLC) is expanding. Patients with EGFR-mutant NSCLC can derive significant benefit from EGFR tyrosine kinase inhibitor (TKI) therapy, including the third-generation EGFR TKI osimertinib. However, invariably, all patients will experience disease progression with this therapy mainly due to the adaptation of cancer cells through primary or secondary molecular mechanisms of resistance. The comprehension and access to tissue and cell-free DNA next-generation sequencing have fueled the development of innovative therapeutic strategies to prevent and overcome resistance to osimertinib in the clinical setting. Herein, we review the biological and clinical implications of molecular mechanisms of osimertinib resistance and the ongoing development of therapeutic strategies to overcome or prevent resistance.
Phase II Investigation of TVB-2640 (Denifanstat) with Bevacizumab in Patients with First Relapse High-Grade Astrocytoma
Authors: Kelly William , Diaz Duque Adolfo Enrique , Michalek Joel , Konkel Brandon , Caflisch Laura , Chen Yidong , Pathuri Sarath Chand , Madhusudanannair-Kunnuparampil Vinu , Floyd John , Brenner Andrew 
Published: April 2023

Abstract

Purpose:
Glioblastoma represents the most common primary brain tumor. Although antiangiogenics are used in the recurrent setting, they do not prolong survival. Glioblastoma is known to upregulate fatty acid synthase (FASN) to facilitate lipid biosynthesis. TVB-2640, a FASN inhibitor, impairs this activity.

Patients and Methods:
We conducted a prospective, single-center, open-label, unblinded, phase II study of TVB-2640 plus bevacizumab in patients with recurrent high-grade astrocytoma. Patients were randomly assigned to TVB-2640 (100 mg/m2 oral daily) plus bevacizumab (10 mg/kg i.v., D1 and D15) or bevacizumab monotherapy for cycle 1 only (28 days) for biomarker analysis. Thereafter, all patients received TVB-2640 plus bevacizumab until treatment-related toxicity or progressive disease (PD). The primary endpoint was progression-free survival (PFS).

Results:
A total of 25 patients were enrolled. The most frequently reported adverse events (AE) were palmar–plantar erythrodysesthesia, hypertension, mucositis, dry eye, fatigue, and skin infection. Most were grade 1 or 2 in intensity. The overall response rate (ORR) for TVB-2640 plus bevacizumab was 56% (complete response, 17%; partial response, 39%). PFS6 for TVB-2640 plus bevacizumab was 31.4%. This represented a statistically significant improvement in PFS6 over historical bevacizumab monotherapy (BELOB 16%; P = 0.008) and met the primary study endpoint. The observed OS6 was 68%, with survival not reaching significance by log-rank test (P = 0.56).

Conclusions:
In this phase II study of relapsed high-grade astrocytoma, TVB-2640 was found to be a well-tolerated oral drug that could be safely combined with bevacizumab. The favorable safety profile and response signals support the initiation of a larger multicenter trial of TVB-2640 plus bevacizumab in astrocytoma.
A Phase I/II Trial of HER2 Vaccine–Primed Autologous T-Cell Infusions in Patients with Treatment Refractory HER2–Overexpressing Breast Cancer
Authors: Disis Mary L. , Dang Yushe , Coveler Andrew L. , Childs Jennifer S. , Higgins Doreen M. , Liu Ying , Zhou Jing , Mackay Sean , Salazar Lupe G. 
Published: April 2023

Abstract

Purpose:
High levels of type I T cells are needed for tumor eradication. We evaluated whether the HER2-specific vaccine–primed T cells are readily expanded ex vivo to achieve levels needed for therapeutic infusion.

Patients and Methods:
Phase I/II nonrandomized trial of escalating doses of ex vivo–expanded HER2-specific T cells after in vivo priming with a multiple peptide–based HER2 intracellular domain (ICD) vaccine. Vaccines were given weekly for a total of three immunizations. Two weeks after the third vaccine, patients underwent leukapheresis for T-cell expansion, then received three escalating cell doses over 7- to 10-day intervals. Booster vaccines were administered after the T-cell infusions. The primary objective was safety. The secondary objectives included extent and persistence of HER2-specific T cells, development of epitope spreading, and clinical response. Patients received a CT scan prior to enrollment and 1 month after the last T-cell infusion.

Results:
Nineteen patients received T-cell infusions. Treatment was well tolerated. One month after the last T-cell infusion, 82% of patients had significantly augmented T cells to at least one of the immunizing epitopes and 81% of patients demonstrated enhanced intramolecular epitope spreading compared with baseline (P &lt; 0.05). There were no complete responses, one partial response (6%), and eight patients with stable disease (47%), for a disease control rate of 53%. The median survival for those with progressive disease was 20.5 months and for responders (PR+SD) was 45.0 months.

Conclusions:
Adoptive transfer of HER2 vaccine–primed T cells was feasible, was associated with minimal toxicity, and resulted in an increased overall survival in responding patients.
See related commentary by Crosby et al., p. 3256
The Emerging Role of Circulating Tumor DNA in Non-Colorectal Gastrointestinal Cancers
Authors: Lee Michael S. , Kaseb Ahmed O. , Pant Shubham 
Published: April 2023

Abstract
Assays to detect circulating tumor DNA (ctDNA) have multiple clinically important applications in management of multiple types of gastrointestinal cancers. Different methodologies of ctDNA detection have varying sensitivities and potential applications in different contexts. For patients with localized cancers treated for curative intent, ctDNA detection is associated with prognosis in multiple cancer types, and persistent detection of ctDNA after surgical resection is highly concerning for minimal residual disease (MRD) and forebodes impending radiographic and clinical recurrence. CtDNA assays for comprehensive genomic profiling enable genotyping of cancers in the absence of tumor tissue data, and longitudinal testing can also characterize clonal evolution and emergence of putative resistance mechanisms upon treatment with targeted agents. These applications have proven instructive in patients with HER2-amplified gastric and esophageal cancers and in patients with FGFR2 fusion cholangiocarcinomas. In this review, we summarize data supporting the role of ctDNA as a novel predictive and prognostic biomarker and potential impacts on current management of patients with pancreatic, gastroesophageal, and hepatobiliary cancers.
First-in-Human Study of the Radioligand 68Ga-N188 Targeting Nectin-4 for PET/CT Imaging of Advanced Urothelial Carcinoma
Authors: Duan Xiaojiang , Xia Lei , Zhang Zhuochen , Ren Yanan , Pomper Martin G. , Rowe Steven P. , Li Xuesong , Li Nan , Zhang Ning , Zhu Hua , Yang Zhi , Sheng Xinan , Yang Xing 
Published: April 2023

Abstract

Purpose:
Nectin-4 is an emerging biomarker for cancer diagnosis and therapy. Recently, enfortumab vedotin (EV) was approved by the FDA as the first nectin-4 targeting antibody–drug conjugate for treating advanced urothelial carcinoma (UC). A PET imaging method to noninvasively quantify nectin-4 expression level would potentially help to select patients most likely to respond to EV and predict the response.

Experimental Design:
In this study, we designed a bicyclic peptide-based nectin-4 targeting radiotracer 68Ga-N188. Initially, we performed preclinical evaluations of 68Ga-N188 in UC cell lines and xenograft mouse models. Next, we performed the translational study in healthy volunteers and a pilot cohort of patients with advanced UC on uEXPLORER total-body PET/CT.

Results:
In the preclinical study, 68Ga-N188 showed high affinity to nectin-4, specific uptake in a nectin-4(+) xenograft mouse model, and suitable pharmacokinetic and safety profiles. In the translational study, 2 healthy volunteers and 14 patients with advanced UC were enrolled. The pharmacokinetic profile was determined for 68Ga-N188, and the nectin-4 relative expression level in different organs was quantitatively imaged.

Conclusions:
A clear correlation between PET SUV value and nectin-4 expression was observed, supporting the application of 68Ga-N188 PET as a companion diagnostic tool for optimizing treatments that target nectin-4.
See related commentary by Jiang et al., p. 3259
Projected Global Trends in Ischemic Stroke Incidence, Deaths and Disability-Adjusted Life Years From 2020 to 2030
Authors: Pu Liyuan , Wang Li , Zhang Ruijie , Zhao Tian , Jiang Yannan , Han Liyuan 
Published: April 2023

Background:
We projected global trends in ischemic stroke from 2020 to 2030 according to age, sex, and socio-demographic index (SDI) quintile.

Methods:
Estimated annual percentage changes (EAPCs) were used to project trends in the incidence of deaths from and disability-adjusted life years (DALYs) due to ischemic stroke between 2020 and 2030. EAPCs were computed using generalized additive models and data from the Global Burden of Disease study during the 1990 to 2019 period.

Results:
The global age-standardized incidence rate of ischemic stroke was projected to increase to 89.32 per 100 000 population in 2030 (EAPC=0.89), whereas the associated global age-standardized death and DALY rates were projected to decrease to 18.28 (EAPC, −3.58) and 500.37 per 100 000 (EAPC=−1.75), respectively, in 2030. The projections indicated a higher age-standardized incidence rate of ischemic stroke among women than among men in 2030 (90.70 versus 87.64 per 100 000). The incidence rate of ischemic stroke was projected to increase across all age groups and SDI quintiles between 2020 and 2030. At the national level, the greatest increase in the age-standardized incidence rate of ischemic stroke between 2020 and 2030 was projected to occur in Cyprus (EAPC=4.16), followed by Palestine (EAPC=3.50) and South Africa (EAPC=2.64). Additionally, the projections suggested increases in the age-standardized death and DALY rates due to ischemic stroke for countries in low-SDI quintiles (EAPC=3.68 and EAPC=5.30, respectively).

Conclusions:
The projections indicated that the incidence rate of ischemic stroke will increase both sexes, all age groups, and all SDI quintiles and in some countries between 2020 and 2030. Furthermore, countries with a low SDI should be aware of potential increases in the age-standardized death and DALY due to ischemic stroke.
Sex and Racial Disparity in Outcome of Aneurysmal Subarachnoid Hemorrhage in the United States: A 20-Year Analysis
Authors: Schupper Alexander J. , Hardigan Trevor A. , Mehta Amol , Yim Benjamin , Yaeger Kurt A. , De Leacy Reade , Fifi Johanna T. , Mocco J , Majidi Shahram 
Published: April 2023

Background:
Aneurysmal subarachnoid hemorrhage is associated with high rate of morbidity and mortality. We aimed to assess prognostic impact of sex, race, and ethnicity in these patients.

Methods:
Nationwide Inpatient Sample (2000–2019) was used to identify patients presenting with aneurysmal subarachnoid hemorrhage as primary diagnosis. Patient age, sex, race/ethnicity, insurance status, socioeconomic status, comorbidities, type of the hospital, and treatment modality used for aneurysm repair were extracted. The previously validated Nationwide Inpatient Sample Subarachnoid Hemorrhage Severity Scale was used to estimate the clinical severity. Discharge destination and in-hospital mortality was used as outcome measured. The impact of race/ethnicity and sex on clinical outcome was analyzed using multivariate regression models.

Results:

A total of 161 086 patients with aneurysmal subarachnoid hemorrhage were identified. Mean age was 55.0±13.8 years. Sixty-nine percent of the patients were female, 60% White patients, and 17% Black patients. There was no difference in the Nationwide Inpatient Sample Subarachnoid Hemorrhage Severity Scale score between the 2 sexes. Women had significantly lower odds of good clinical outcome (defined as discharge to home or acute rehabilitation facility; RR, 0.83 [95% CI, 0.74–0.94];
P
=0.004). Hispanic patients (RR, 1.12 [95% CI, 1.07–1.17];
P
<0.001) had higher odds of excellent clinical outcome compared with White patients, and lower risk of mortality were observed in Black patients (RR, 0.73 [95% CI, 0.66–0.81]) and Hispanic patients (RR, 0.78 [95% CI, 0.70–0.86]) compared with the White patients.

Conclusions:
In this nationally representative study, women were less likely to have excellent outcomes following aneurysmal subarachnoid hemorrhage, and White patients had disproportionately higher likelihood of worse clinical outcomes. Lower rates of mortality were seen among Black and Hispanic patients.
Deep Learning Algorithm Enables Cerebral Venous Thrombosis Detection With Routine Brain Magnetic Resonance Imaging
Authors: Yang Xiaoxu , Yu Pengxin , Zhang Haoyue , Zhang Rongguo , Liu Yuehong , Li Haoyuan , Sun Penghui , Liu Xin , Wu Yu , Jia Xiuqin , Duan Jiangang , Ji Xunming , Yang Qi 
Published: April 2023

Background:
Cerebral venous thrombosis (CVT) is a rare cerebrovascular disease. Routine brain magnetic resonance imaging is commonly used to diagnose CVT. This study aimed to develop and evaluate a novel deep learning (DL) algorithm for detecting CVT using routine brain magnetic resonance imaging.

Methods:
Routine brain magnetic resonance imaging, including T1-weighted, T2-weighted, and fluid-attenuated inversion recovery images of patients suspected of CVT from April 2014 through December 2019 who were enrolled from a CVT registry, were collected. The images were divided into 2 data sets: a development set and a test set. Different DL algorithms were constructed in the development set using 5-fold cross-validation. Four radiologists with various levels of expertise independently read the images and performed diagnosis within the test set. The diagnostic performance on per-patient and per-segment diagnosis levels of the DL algorithms and radiologist’s assessment were evaluated and compared.

Results:

A total of 392 patients, including 294 patients with CVT (37±14 years, 151 women) and 98 patients without CVT (42±15 years, 65 women), were enrolled. Of these, 100 patients (50 CVT and 50 non-CVT) were randomly assigned to the test set, and the other 292 patients comprised the development set. In the test set, the optimal DL algorithm (multisequence multitask deep learning algorithm) achieved an area under the curve of 0.96, with a sensitivity of 96% (48/50) and a specificity of 88% (44/50) on per-patient diagnosis level, as well as a sensitivity of 88% (129/146) and a specificity of 80% (521/654) on per-segment diagnosis level. Compared with 4 radiologists, multisequence multitask deep learning algorithm showed higher sensitivity both on per-patient (all
P
<0.05) and per-segment diagnosis levels (all
P
<0.001).

Conclusions:
The CVT-detected DL algorithm herein improved diagnostic performance of routine brain magnetic resonance imaging, with high sensitivity and specificity, which provides a promising approach for detecting CVT.
Global Horizontal Irradiance in West Africa: Evaluation of the WRF-Solar Model in Convection-Permitting Mode with Ground Measurements
Authors: Sawadogo Windmanagda , Bliefernicht Jan , Fersch Benjamin , Salack Seyni , Guug Samuel , Ogunjobi Kehinde O. , Meilinger Stefanie , Kunstmann Harald 
Published: April 2023

Abstract
The number of solar power plants has increased in West Africa in recent years. Reliable reanalysis data and short-term forecasting of solar irradiance from numerical weather prediction models could provide an economic advantage for the planning and operation of solar power plants, especially in data-poor regions such as West Africa. This study presents a detailed assessment of different shortwave (SW) radiation schemes from the Weather Research and Forecasting (WRF) Model option Solar (WRF-Solar), with appropriate configurations for different atmospheric conditions in Ghana and the southern part of Burkina Faso. We applied two 1-way nested domains (D1 = 15 km and D2 = 3 km) to investigate four different SW schemes, namely, the Community Atmosphere Model, Dudhia, RRTMG, Goddard, and RRTMG without aerosol and with aerosol inputs (RRTMG_AERO). The simulation results were validated using hourly measurements from different automatic weather stations established in the study region in recent years. The results show that the RRTMG_AERO_D01 generally outperforms the other SW radiation schemes to simulate global horizontal irradiance under all-sky condition [RMSE = 235 W m−2 (19%); MAE = 172 W m−2 (14%)] and also under cloudy skies. Moreover, RRTMG_AERO_D01 shows the best performance on a seasonal scale. Both the RRTMG_AERO and Dudhia experiments indicate a good performance under clear skies. However, the sensitivity study of different SW radiation schemes in the WRF-Solar model suggests that RRTMG_AERO gives better results. Therefore, it is recommended that it be used for solar irradiance forecasts over Ghana and the southern part of Burkina Faso.
Nowcasting Multiparameter Phased-Array Weather Radar (MP-PAWR) Echoes of Localized Heavy Precipitation Using a 3D Recurrent Neural Network Trained with an Adversarial Technique
Authors: Baron Philippe , Kawashima Kohei , Kim Dong-Kyun , Hanado Hiroshi , Kawamura Seiji , Maesaka Takeshi , Nakagawa Katsuhiro , Satoh Shinsuke , Ushio Tomoo 
Published: April 2023

Abstract
We present nowcasts of sudden heavy rains on meso-γ scales (2–20 km) using the high spatiotemporal resolution of a multiparameter phased-array weather radar (MP-PAWR) sensitive to rain droplets. The onset of typical storms is successfully predicted with 10-min lead time, i.e., the current predictability limit of rainfall caused by individual convective cores. A supervised recurrent neural network based on long short-term memory with 3D spatial convolutions (RN3D) is used to account for the horizontal and vertical changes of the convective cells with a time resolution of 30 s. The model uses radar reflectivity at horizontal polarization ZH and the differential reflectivity. The input parameters are defined in a volume of 64 × 64 × 8 km3 with the lowest level at 1.9 km and a resolution of 0.4 × 0.4 × 0.25 km3. The prediction is a 10-min sequence of ZH at the lowest grid level. The model is trained with a large number of observations of summer 2020 and an adversarial technique. RN3D is tested with different types of rapidly evolving localized heavy rainfalls of summers 2018 and 2019. The model performance is compared to that of an advection model for 3D extrapolation of PAWR echoes (A3DM). RN3D better predicts the formation and dissipation of precipitation. However, RN3D tends to underestimate heavy rainfall especially when the storm is well developed. In this phase of the storm, A3DM nowcast scores are found slightly higher. The high skill of RN3D to predict the onset of sudden localized rainfall is illustrated with an example for which RN3D outperforms the operational precipitation nowcasting system of Japan Meteorological Agency (JMA).

Significance Statement
Temporal extrapolation of radar observations is a means of nowcasting sudden heavy rains, i.e., forecasts with a few tens of minutes and a high spatial resolution better than 500 m. They are necessary to set up warning systems to anticipate damage to infrastructure and reduce the fatalities these storms cause. It is a difficult task due to the storm suddenness, restricted area, and nonlinear behavior that are not well captured by current operational observation and numerical systems. In this study, we use a new high-resolution weather radar with polarimetric information and a 3D recurrent neural network to improve 10-min nowcasts, the current limit of operational systems. This is a first and essential step before applying such a method for increasing the prediction lead time.