bluuebunny/crossref_metadata_2025_split huggingface dataset:
VCAM-1–targeted MRI Improves Detection of the Tumor-brain Interface
Authors: Cheng Vinton W.T. , de Pennington Nicholas , Zakaria Rasheed , Larkin James R. , Serres Sébastien , Sarkar Manjima , Kirkman Matthew A. , Bristow Claire , Croal Paula , Plaha Puneet , Campo Leticia , Chappell Michael A. , Lord Simon , Jenkinson Michael D. , Middleton Mark R. , Sibson Nicola R. 
Published: March 2022

Abstract

Purpose:
Despite optimal local therapy, tumor cell invasion into normal brain parenchyma frequently results in recurrence in patients with solid tumors. The aim of this study was to determine whether microvascular inflammation can be targeted to better delineate the tumor-brain interface through vascular cell adhesion molecule-1 (VCAM-1)-targeted MRI.

Experimental Design:
Intracerebral xenograft rat models of MDA231Br-GFP (breast cancer) brain metastasis and U87MG (glioblastoma) were used to histologically examine the tumor-brain interface and to test the efficacy of VCAM-1–targeted MRI in detecting this region. Human biopsy samples of the brain metastasis and glioblastoma margins were examined for endothelial VCAM-1 expression.

Results:
The interface between tumor and surrounding normal brain tissue exhibited elevated endothelial VCAM-1 expression and increased microvessel density. Tumor proliferation and stemness markers were also significantly upregulated at the tumor rim in the brain metastasis model. T2*-weighted MRI, following intravenous administration of VCAM-MPIO, highlighted the tumor-brain interface of both tumor models more extensively than gadolinium-DTPA–enhanced T1-weighted MRI. Sites of VCAM-MPIO binding, evident as hypointense signals on MR images, correlated spatially with endothelial VCAM-1 upregulation and bound VCAM-MPIO beads detected histologically. These findings were further validated in an orthotopic medulloblastoma model. Finally, the tumor-brain interface in human brain metastasis and glioblastoma samples was similarly characterized by microvascular inflammation, extending beyond the region detectable using conventional MRI.

Conclusions:
This work illustrates the potential of VCAM-1–targeted MRI for improved delineation of the tumor-brain interface in both primary and secondary brain tumors.
Artificial Intelligence-Assisted Serial Analysis of Clinical Cancer Genomics Data Identifies Changing Treatment Recommendations and Therapeutic Targets
Authors: Fischer Catherine G. , Pallavajjala Aparna , Jiang LiQun , Anagnostou Valsamo , Tao Jessica , Adams Emily , Eshleman James R. , Gocke Christopher D. , Lin Ming-Tseh , Platz Elizabeth A. , Xian Rena R. 
Published: March 2022

Abstract

Purpose:
Given the pace of predictive biomarker and targeted therapy development, it is unknown whether repeat annotation of the same next-generation sequencing data can identify additional clinically actionable targets that could be therapeutically leveraged. In this study, we sought to determine the predictive yield of serial reanalysis of clinical tumor sequencing data.

Experimental Design:
Using artificial intelligence (AI)-assisted variant annotation, we retrospectively reanalyzed sequencing data from 2,219 patients with cancer from a single academic medical center at 3-month intervals totaling 9 months in 2020. The yield of serial reanalysis was assessed by the proportion of patients with improved strength of therapeutic recommendations.

Results:
A total of 1,775 patients (80%) had ≥1 potentially clinically actionable mutation at baseline, including 243 (11%) patients who had an alteration targeted by an FDA-approved drug for their cancer type. By month 9, the latter increased to 458 (21%) patients mainly due to a single pan-cancer agent directed against tumors with high tumor mutation burden. Within this timeframe, 67 new therapies became available and 45 were no longer available. Variant pathogenicity classifications also changed leading to changes in treatment recommendations for 124 patients (6%).

Conclusions:
Serial reannotation of tumor sequencing data improved the strength of treatment recommendations (based on level of evidence) in a mixed cancer cohort and showed substantial changes in available therapies and variant classifications. These results suggest a role for repeat analysis of tumor sequencing data in clinical practice, which can be streamlined with AI support.
Porcupine Inhibition Disrupts Mitochondrial Function and Homeostasis in WNT Ligand–Addicted Pancreatic Cancer
Authors: Aguilera Kristina Y. , Le Thuc , Riahi Rana , Lay Anna R. , Hinz Stefan , Saadat Edris A. , Vashisht Ajay A. , Wohlschlegel James , Donahue Timothy R. , Radu Caius G. , Dawson David W. 
Published: March 2022

Abstract
WNT signaling promotes pancreatic ductal adenocarcinoma (PDAC) through diverse effects on proliferation, differentiation, survival, and stemness. A subset of PDAC with inactivating mutations in ring finger protein 43 (RNF43) show growth dependency on autocrine WNT ligand signaling and are susceptible to agents that block WNT ligand acylation by Porcupine O-acyltransferase, which is required for proper WNT ligand processing and secretion. For this study, global transcriptomic, proteomic, and metabolomic analyses were performed to explore the therapeutic response of RNF43-mutant PDAC to the Porcupine inhibitor (PORCNi) LGK974. LGK974 disrupted cellular bioenergetics and mitochondrial function through actions that included rapid mitochondrial depolarization, reduced mitochondrial content, and inhibition of oxidative phosphorylation and tricarboxylic acid cycle. LGK974 also broadly altered transcriptional activity, downregulating genes involved in cell cycle, nucleotide metabolism, and ribosomal biogenesis and upregulating genes involved in epithelial–mesenchymal transition, hypoxia, endocytosis, and lysosomes. Autophagy and lysosomal activity were augmented in response to LGK974, which synergistically inhibited tumor cell viability in combination with chloroquine. Autocrine WNT ligand signaling dictates metabolic dependencies in RNF43-mutant PDAC through a combination of transcription dependent and independent effects linked to mitochondrial health and function. Metabolic adaptations to mitochondrial damage and bioenergetic stress represent potential targetable liabilities in combination with PORCNi for the treatment of WNT ligand-addicted PDAC.
Cigarette Smoke Containing Acrolein Contributes to Cisplatin Resistance in Human Bladder Cancers through the Regulation of HER2 Pathway or FGFR3 Pathway
Authors: Hong Jian-Hua , Tong Zhen-Jie , Wei Tung-En , Lu Yu-Chuan , Huang Cheng-Yu , Huang Chao-Yuan , Chiang Chih-Hung , Jaw Fu-Shan , Cheng Hsiao-Wei , Wang Hsiang-Tsui 
Published: March 2022

Abstract
Cisplatin-based chemotherapy is the first-line therapy for bladder cancer. However, cisplatin resistance has been associated with the recurrence of bladder cancer. Previous studies have shown that activation of FGFR and HER2 signaling are involved in bladder cancer cell proliferation and drug resistance. Smoking is the most common etiologic risk factor for bladder cancer, and there is emerging evidence that smoking is associated with cisplatin resistance. However, the underlying mechanism remains elusive. Acrolein, a highly reactive aldehyde, is abundant in tobacco smoke, cooking fumes, and automobile exhaust fumes. Our previous studies have shown that acrolein contributes to bladder carcinogenesis through the induction of DNA damage and inhibition of DNA repair. In this study, we found that acrolein induced cisplatin resistance and tumor progression in both non–muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) cell lines RT4 and T24, respectively. Activation of HER2 and FGFR3 signaling contributes to acrolein-induced cisplatin resistance in RT4 and T24 cells, respectively. Furthermore, trastuzumab, an anti-HER2 antibody, and PD173074, an FGFR inhibitor, reversed cisplatin resistance in RT4 and T24 cells, respectively. Using a xenograft mouse model with acrolein-induced cisplatin-resistant T24 clones, we found that cisplatin combined with PD173074 significantly reduced tumor size compared with cisplatin alone. These results indicate that differential molecular alterations behind cisplatin resistance in NMIBC and MIBC significantly alter the effectiveness of targeted therapy combined with chemotherapy. This study provides valuable insights into therapeutic strategies for cisplatin-resistant bladder cancer.
Pharmacologic Activation of STING in the Bladder Induces Potent Antitumor Immunity in Non–Muscle Invasive Murine Bladder Cancer
Authors: Huang Kuan-Chun , Chandra Dinesh , McGrath Shannon , Dixit Vaishali , Zhang Chi , Wu Jiayi , Tendyke Karen , Yao Huilan , Hukkanen Renee , Taylor Noel , Verbel David , Kim Dae-Shik , Endo Atsushi , Noland Thomas A. , Chen Yu , Matijevic Mark , Wang John , Hutz Janna , Sarwar Nadeem , Fang Francis G. , Bao Xingfeng 
Published: March 2022

AbstractStimulator of interferon genes (STING) is an innate immune receptor activated by natural or synthetic agonists to elicit antitumoral immune response via type I IFNs and other inflammatory cytokines. Bacillus Calmette-Guerin (BCG) is the standard of care as intravesical therapy for patients with high-risk non–muscle invasive bladder cancer (NMIBC). There are limited options available for patients with NMIBC who developed BCG unresponsiveness. In this study, we characterized in vitro and in vivo antitumor effects of E7766, a macrocyle-bridged STING agonist, via intravesical instillation in two syngeneic orthotopic murine NMIBC tumor models resistant to therapeutic doses of BCG and anti–PD-1 agents. E7766 bound to recombinant STING protein with a Kd value of 40 nmol/L and induced IFNβ expression in primary human peripheral blood mononuclear cells harboring any of seven major STING genotypes with EC50 values of 0.15 to 0.79 μmol/L. Intravesical E7766 was efficacious in both NMIBC models with induction of effective immunologic memory in the treated animals. Pharmacologic activation of the STING pathway in the bladder resulted in IFN pathway activation, infiltration of T cells and natural killer (NK) cells, dendritic cell activation, and antigen presentation in bladder epithelium, leading to the antitumor activity and immunity. In addition, measurements of the pharmacodynamic markers, Ifnβ1 and CXCL10, in bladder, urine, and plasma, and of STING pathway intactness in cancer cells, supported this mode of action. Taken together, our studies reveal an antitumor immune effect of pharmacologic activation of the STING pathway in bladder epithelium and thus provide a rationale for subsequent clinical studies in patients with NMIBC.
Comprehensive Surfaceome Profiling to Identify and Validate Novel Cell-Surface Targets in Osteosarcoma
Authors: Wang Yifei , Tian Xiangjun , Zhang Wendong , Zhang Zhongting , Lazcano Rossana , Hingorani Pooja , Roth Michael E. , Gill Jonathan D. , Harrison Douglas J. , Xu Zhaohui , Jusu Sylvester , Kannan Sankaranarayanan , Wang Jing , Lazar Alexander J. , Earley Eric J. , Erickson Stephen W. , Gelb Tara , Huxley Philip , Lahdenranta Johanna , Mudd Gemma , Kurmasheva Raushan T. , Houghton Peter J. , Smith Malcolm A. , Kolb Edward A. , Gorlick Richard 
Published: March 2022

Abstract
Immunoconjugates targeting cell-surface antigens have demonstrated clinical activity to enable regulatory approval in several solid and hematologic malignancies. We hypothesize that a rigorous and comprehensive surfaceome profiling approach to identify osteosarcoma-specific cell-surface antigens can similarly enable development of effective therapeutics in this disease. Herein, we describe an integrated proteomic and transcriptomic surfaceome profiling approach to identify cell-surface proteins that are highly expressed in osteosarcoma but minimally expressed on normal tissues. Using this approach, we identified targets that are highly expressed in osteosarcoma. Three targets, MT1-MMP, CD276, and MRC2, were validated as overexpressed in osteosarcoma. Furthermore, we tested BT1769, an MT1-MMP–targeted Bicycle toxin conjugate, in osteosarcoma patient-derived xenograft models. The results showed that BT1769 had encouraging antitumor activity, high affinity for its target, and a favorable pharmacokinetic profile. This confirms the hypothesis that our approach identifies novel targets with significant therapeutic potential in osteosarcoma.
“From Scenic Interpretation to Fluent Speaking: Literary Texts “Linie 1” in the German Classroom”
Authors: Cansrina Genita , Gantrisia Kamelia , Ratnasari Dewi 
Published: March 2022

These article explores the question of how literary texts can be didactizised in foreign language classroom. Based on the hypothesis that the students are still shy and reserved despite the sufficient knowledge of German, the main goal of this research ist an attempt to make the learners speak. Scenic interpretation, whose term originated from the scenic play, was concepted by Scheller (1996) in order to give literature back its meaning when he noticed the students showed a distance to foreign literary texts. This method connected the theater pedagogy with the teaching of German as a foreign language, in which two central orientations can be distinguished, namely process orientation and product orientation. In the field of foreign language acquisition, this method serves to improve oral communication skills and thus a process-oriented orientation is pursued. If one considers scenic interpretation as a methodological approach in German teaching, teaching with the means of theater is part of an action-oriented teaching, in which the students are in the center, because they themselves are active and the teacher gets more the tasks as an organizer of the learning process. The selected corpus of this research ist “Linie 1”, a musical revue by Ludwig (2007), in which Berlin dialect can be often be heard as one of the signs of authentic conversation in the scenes of subway. Not only from hearing, but also from seeing, learners get input from this musical performance, through which it is assumed that it is easier for them to imagine the spaces, the situation, the relationship and the images to interpret the texts. In order to make the students aware of the contrastive considerations, questionnaires are distributed to them, in which a few questions are asked according to the learner´s sensations. Furthermore, these literary texts are didactizised using the Four Strands model developed by Paul Nation (2007). The preliminary result of this research can be said, that after one semester sessions, the students speak more fluently because they are familiarized with the text and therefore they have more self-confidence.
Time-Aware Language Models as Temporal Knowledge Bases
Authors: Dhingra Bhuwan , Cole Jeremy R. , Eisenschlos Julian Martin , Gillick Daniel , Eisenstein Jacob , Cohen William W. 
Published: March 2022

Abstract
Many facts come with an expiration date, from the name of the President to the basketball team Lebron James plays for. However, most language models (LMs) are trained on snapshots of data collected at a specific moment in time. This can limit their utility, especially in the closed-book setting where the pretraining corpus must contain the facts the model should memorize. We introduce a diagnostic dataset aimed at probing LMs for factual knowledge that changes over time and highlight problems with LMs at either end of the spectrum—those trained on specific slices of temporal data, as well as those trained on a wide range of temporal data. To mitigate these problems, we propose a simple technique for jointly modeling text with its timestamp. This improves memorization of seen facts from the training time period, as well as calibration on predictions about unseen facts from future time periods. We also show that models trained with temporal context can be efficiently “refreshed” as new data arrives, without the need for retraining from scratch.
Persistent Discrepancies between Observed and Modeled Trends in the Tropical Pacific Ocean
Authors: Seager Richard , Henderson Naomi , Cane Mark 
Published: March 2022

Abstract
The trends over recent decades in tropical Pacific sea surface and upper ocean temperature are examined in observations-based products, an ocean reanalysis and the latest models from the Coupled Model Intercomparison Project phase six and the Multimodel Large Ensembles Archive. Comparison is made using three metrics of sea surface temperature (SST) trend—the east–west and north–south SST gradients and a pattern correlation for the equatorial region—as well as change in thermocline depth. It is shown that the latest generation of models persist in not reproducing the observations-based SST trends as a response to radiative forcing and that the latter are at the far edge or beyond the range of modeled internal variability. The observed combination of thermocline shoaling and lack of warming in the equatorial cold tongue upwelling region is similarly at the extreme limit of modeled behavior. The persistence over the last century and a half of the observed trend toward an enhanced east–west SST gradient and, in four of five observed gridded datasets, to an enhanced equatorial north–south SST gradient, is also at the limit of model behavior. It is concluded that it is extremely unlikely that the observed trends are consistent with modeled internal variability. Instead, the results support the argument that the observed trends are a response to radiative forcing in which an enhanced east–west SST gradient and thermocline shoaling are key and that the latest generation of climate models continue to be unable to simulate this aspect of climate change.
How China’s Fengyun Satellite Precipitation Product Compares with Other Mainstream Satellite Precipitation Products
Authors: Sun Zhangli , Long Di , Hong Zhongkun , Hamouda Mohamed A. , Mohamed Mohamed M. , Wang Jianhua 
Published: March 2022

AbstractSatellite-based and reanalysis precipitation estimates are an alternative and important supplement to rain gauge data. However, performance of China’s Fengyun (FY) satellite precipitation product and how it compares with other mainstream satellite and reanalysis precipitation products over China remain largely unknown. Here five satellite-based precipitation products (i.e., FY-2 precipitation product, IMERG, GSMaP, CMORPH, and PERSIANN-CDR) and one reanalysis product (i.e., ERA5) are intercompared and evaluated based on in situ daily precipitation measurements over mainland China during 2007–17. Results show that the performance of these precipitation products varies with regions and seasons, with better statistical metrics over wet regions and during warm seasons. The infrared–microwave combined precipitation [i.e., IMERG, GSMaP, and CMORPH, with median KGE (Kling–Gupta efficiency) values of 0.53, 0.52, 0.59, respectively] reveals better performance than the infrared-based only product (i.e., PERSIANN-CDR, with a median KGE of 0.31) and the reanalysis product (i.e., ERA5, with a median KGE of 0.43). IMERG performs well in retrieving precipitation intensity and occurrence over China, while GSMaP performs well in the middle to low reaches of the Yangtze River basin but poorly over sparsely gauged regions, e.g., Xinjiang in northwest China and the Tibetan Plateau. CMORPH performs well over most regions and has a greater ability to detect precipitation events than GSMaP. The FY-2 precipitation product can capture the overall spatial distribution of precipitation in terms of both precipitation intensity and occurrence (median KGE and CSI of 0.54 and 0.55), and shows better performance than other satellite precipitation products in winter and over sparsely gauged regions. Annual precipitation from different products is generally consistent, though underestimation exists in the FY-2 precipitation product during 2015–17.Significance StatementIntercomparison between the FY-2 precipitation product and mainstream precipitation products is valuable to guide applications of satellite precipitation products to China and its subregions. This study illustrates uncertainties in various satellite precipitation products, and could guide optimization of algorithms of precipitation retrieval and data fusion/merging to improve the accuracy and resolution of satellite precipitation products.
Seasonal Climate Effects on Influenza–Pneumonia Mortality and Public Health
Authors: Jury Mark R. , Kerr Jane 
Published: March 2022

Abstract
We study how seasonal climate affects influenza–pneumonia (I-P) mortality using monthly health and climate data over the past 20 years, reduced to mean annual cycle and statistically correlated. Results show that I-P deaths are inversely related to temperature, humidity, and net solar radiation in the United States, South Africa, and Puerto Rico (r < −0.93) via transmission and immune system response. The I-P mortality is 3–10 times as high in winter as in summer, with sharp transitions in autumn and spring. Public health management can rely on seasonal climate-induced fluctuations of I-P mortality to promote healthy lifestyle choices and guide efforts to mitigate epidemic impacts.
Rhabdomyosarcoma Arising in an Old Rhytidectomy Scar
Authors: Ruthberg Jeremy S. , Meleca Joseph B. , Ko Jennifer S. , Billings Steven D. , Ku Jamie A. 
Published: March 2022

Objective: The clinical evaluation and management of an adult with head and neck rhabdomyosarcoma is explored to delineate the diagnostic challenge posed by soft-tissue sarcomas bordering scar tissue. Case Report: A 59 year old female presents with persistent, evolving paresthesia and burning in the right posterior neck, which was found to be in close proximity to a well-healed rhytidectomy scar. Serial biopsies were non-diagnostic. Six months after initial presentation, rhabdomyosarcoma was diagnosed subsequent to histopathological and immunohistochemistry analysis. A wide local excision with posterolateral neck dissection was performed. Conclusion: A high index of suspicion for soft-tissue sarcoma should be maintained for patients with persistent soft-tissue lesions, especially in areas of scarred tissue, who present with new-onset neurological symptoms in the context of nondiagnostic biopsies.