bluuebunny/crossref_metadata_2025 huggingface dataset:
PIMSAB: A Processing-In-Memory System with Spatially-Aware Communication and Bit-Serial-Aware Computation
Authors: Ma Siyuan , Mhatre Kaustubh , Weng Jian , Hanindhito Bagus , Wang Zhengrong , Nowatzki Tony , John Lizy , Arora Aman
Published: September 2024

Bit-serial Processing-In-Memory (PIM) is an attractive paradigm for accelerator architectures, for parallel workloads such as Deep Learning (DL), because of its capability to achieve massive data parallelism at a low area overhead and provide orders-of-magnitude data movement savings by moving computational resources closer to the data. While many PIM architectures have been proposed, improvements are needed in communicating intermediate results to consumer kernels, for communication between tiles at scale, for reduction operations, and for efficiently performing bit-serial operations with constants. We present PIMSAB, a scalable architecture that provides a spatially aware communication network for efficient intra-tile and inter-tile data movement and provides efficient computation support for generally inefficient bit-serial compute patterns. Our architecture consists of a massive hierarchical array of compute-enabled SRAMs (CRAMs), which is codesigned with a compiler to achieve high utilization. The key novelties of our architecture are (1) in providing efficient support for spatially aware communication by providing local H-tree network for reductions, by adding explicit hardware for shuffling operands, and by deploying systolic broadcasting, as well as (2) by taking advantage of the divisible nature of bit-serial computations through adaptive precision and efficient handling of constant operations. These innovations are integrated into a tensor expressions-based programming framework (including a compiler for easy programmability) that enables simple programmer control of optimizations for mapping programs into massively parallel binaries for millions of PIM processing elements. When compared against a similarly provisioned modern Tensor Core GPU (NVIDIA A100), across common DL kernels and end-to-end DL networks (Resnet18 and BERT), PIMSAB outperforms the GPU by 4.80×, and reduces energy by 3.76×. We compare PIMSAB with similarly provisioned state-of-the-art SRAM PIM (Duality Cache) and DRAM PIM (SIMDRAM), and observe a speedup of 3.7× and 3.88×, respectively.
Limit Cycle on the Forced Vibrations Oscillator with a Time‐Varying Mass
Authors: Hartono  , Binatari N. , Saptaningtyas F. Y. , Emut
Published: September 2024

In this paper, a forced vibration caused by drag and lift forces with time‐varying mass is studied. The construction of the model is conducted by adding impact force to the previous model. The periodicity of the solution is yet known. Hence, the model is seen as a perturbation problem. Since the unperturbed problem has a periodic solution, we applied the averaging method to determine the sufficient condition such that the limit cycle exists.
Effectiveness of External Precooling and Vibration Induced by BUZZY on Pain and Anxiety During Inferior Alveolar Nerve Block Injection in Children
Authors: Narimany Reyhane , Faghihian Reyhaneh , Jafarzadeh Samani Mehdi
Published: September 2024

Purpose: Children’s fear of the injection of local anesthetic agents affects their cooperation in pediatric dentistry. Different techniques are available to decrease the injection pain, including the use of precooling agents or vibrators. The present study investigated the effectiveness of Buzzy (Buzzy MMJ Labs, Atlanta, GA, USA). This device transfers cold and external vibration to the injection site during the inferior alveolar nerve block (IANB) injection.

Materials and Methods: The present self‐control, randomized, and double‐blind clinical trial evaluated 30 children aged 6–12, who had bilateral mandibular permanent or primary carious molar teeth. On one side, the BUZZY was applied before and during the IANB injection, and the other side was considered as control. On both sides, a topical anesthetic gel was applied before injection. The pain severity and children’s anxiety were determined using Wong–Baker, face, leg, activity, cry, consolability (FLACC) scales, and the heart rate.

Results: The mean age of the participants was 7.18 ± 1.5 years, with 12 girls and 18 boys. The Wong–Baker scale and FLACC scale did not show any statistically significant difference between BUZZY and control (p value = 0.9 and 0.15, respectively). In addition, BUZZY tool did not significantly decrease pain and anxiety during injection, assessed through the heart rate difference (p = 0.38).

Conclusion: Under the limitations of the present study, a combination of precooling and vibration using the BUZZY device did not decrease pain and anxiety in children during the IANB injection.
Interrupted Aortic Arch: Assessment of Morphology and Associated Cardiovascular Anomalies on Computed Tomography Angiography
Authors: Pujitha Vidiyala , Pandey Niraj Nirmal , Verma Mansi , Kumar Sanjeev , Ramakrishnan Sivasubramanian , Jagia Priya
Published: September 2024

Aim. The present study sought to evaluate the cardiovascular morphology and associated anomalies in patients with interrupted aortic arch (IAA) on CT angiography. Materials and Methods. A retrospective review of our departmental database was conducted to identify patients diagnosed with IAA on CT angiography between January 2014 and September 2022. The demographic information, anatomic characteristics, and associated cardiovascular abnormalities in patients with IAA were assessed. The morphological types of IAA were described in accordance with Celoria–Patton classification. Results. IAA was seen in 49 patients (32 males and 17 females; mean age: 15.9 months). The most common type of IAA based on the site of interruption was type A seen in 27/49 (55.1%) patients, while type B was observed in 22/49 (44.9%) patients. No patient of type C IAA was encountered in the current series. The most commonly associated cardiovascular anomaly was patent ductus arteriosus (PDA) seen in 45/49 (91.8%) patients. Atrial septal defect was seen in 15/49 (30.6%) patients, while 39/49 (79.6%) patients had a ventricular septal defect (VSD). Common arterial trunk was the most common abnormal ventriculo‐arterial connection seen in 13/49 (26.5%) patients. Aorto‐pulmonary window was associated with 7/49 (14.3%) patients. Conclusion. IAA is a rare congenital heart defect associated with an array of cardiovascular anomalies, most common being PDA and VSD. CT angiography is useful not only in diagnosing and characterizing the IAA but also in identifying associated anomalies which may have a bearing on the clinical presentation, prognosis, and surgical management.
Continuous Monitoring of Water Levels for Industrial Boilers Using Single‐Stage Object Recognition YOLOv5
Authors: Kim Jongwon , Kwon Minjun , So Byeongchan , Kim Sewon , So Hongyun
Published: September 2024

This paper presents a measurement method that utilizes object recognition technology for continuous and quantitative real‐time monitoring of water levels in industrial boilers. Real‐time videos of water levels were monitored using a small camera, and the YOLO algorithm, a single‐stage detector, was employed to use the bounding boxes of detected objects within the video as variables, directly measuring the length ratio for each frame. The method demonstrated a high level of accuracy in water‐level measurement, with an average of 99.02%, and a stable performance, with a fluctuation of 0.13% in continuous measurements. Consequently, the proposed measurement method proves feasible for quantifying continuous water levels in industrial inspection systems even in low‐resource environments. These results demonstrate a new mechanism for monitoring technology, without requiring text detection, showing the potential for improving efficiency in complex boiler systems and the feasibility of reliable water‐level measurement and control.
Efficiency Evaluation for Regional Energy and Environment Using Two‐Stage DEA Model Considering Stochastic Factors
Authors: Sun Yi , Gan Lu , Chen Yingchun , Lev Benjamin , Zhou Ying
Published: September 2024

Energy consumption has risen much more while the economy has expanded so quickly. As a result, significant environmental contamination is created, which causes public worry. Under this background, enhancing energy efficiency and lowering pollution is particularly crucial for the fulfillment of sustainable economic development. Efficiency evaluation for energy and environment is an effective measure to achieve both energy saving and emission reduction as well as sustainable social development. In this paper, energy and environmental efficiency consists of energy utilization efficiency and pollution treatment efficiency. An improved two‐stage DEA model is proposed, which takes into account how stochastic and environmental factors affect decision‐making units (DMUs). Finally, the author analyses the panel data of 15 cities in Southwest China from 2010 to 2018, which proves the feasibility and effectiveness of this study. The results show Southwest China’s poor energy and environmental efficiency as well as the stark differences among its cities. The scientific value revealed by this paper is as follows: (1) for the study of energy and environmental efficiency, this paper is more targeted at the differences between cities and (2) using an improved two‐stage DEA model to consider the effects of stochastic factors on DMUs.
Figure S8 from A Pan-Cancer Patient-Derived Xenograft Histology Image Repository with Genomic and Pathologic Annotations Enables Deep Learning Analysis
Authors: White Brian S. , Woo Xing Yi , Koc Soner , Sheridan Todd , Neuhauser Steven B. , Wang Shidan , Evrard Yvonne A. , Chen Li , Foroughi pour Ali , Landua John D. , Mashl R. Jay , Davies Sherri R. , Fang Bingliang , Raso Maria Gabriela , Evans Kurt W. , Bailey Matthew H. , Chen Yeqing , Xiao Min , Rubinstein Jill C. , Sanderson Brian J. , Lloyd Michael W. , Domanskyi Sergii , Dobrolecki Lacey E. , Fujita Maihi , Fujimoto Junya , Xiao Guanghua , Fields Ryan C. , Mudd Jacqueline L. , Xu Xiaowei , Hollingshead Melinda G. , Jiwani Shahanawaz , Acevedo Saul , Davis-Dusenbery Brandi N. , Robinson Peter N. , Moscow Jeffrey A. , Doroshow James H. , Mitsiades Nicholas , Kaochar Salma , Pan Chong-xian , Carvajal-Carmona Luis G. , Welm Alana L. , Welm Bryan E. , Govindan Ramaswamy , Li Shunqiang , Davies Michael A. , Roth Jack A. , Meric-Bernstam Funda , Xie Yang , Herlyn Meenhard , Ding Li , Lewis Michael T. , Bult Carol J. , Dean Dennis A. , Chuang Jeffrey H.
Published: September 2024

Figure S8
Figure S5 from A Pan-Cancer Patient-Derived Xenograft Histology Image Repository with Genomic and Pathologic Annotations Enables Deep Learning Analysis
Authors: White Brian S. , Woo Xing Yi , Koc Soner , Sheridan Todd , Neuhauser Steven B. , Wang Shidan , Evrard Yvonne A. , Chen Li , Foroughi pour Ali , Landua John D. , Mashl R. Jay , Davies Sherri R. , Fang Bingliang , Raso Maria Gabriela , Evans Kurt W. , Bailey Matthew H. , Chen Yeqing , Xiao Min , Rubinstein Jill C. , Sanderson Brian J. , Lloyd Michael W. , Domanskyi Sergii , Dobrolecki Lacey E. , Fujita Maihi , Fujimoto Junya , Xiao Guanghua , Fields Ryan C. , Mudd Jacqueline L. , Xu Xiaowei , Hollingshead Melinda G. , Jiwani Shahanawaz , Acevedo Saul , Davis-Dusenbery Brandi N. , Robinson Peter N. , Moscow Jeffrey A. , Doroshow James H. , Mitsiades Nicholas , Kaochar Salma , Pan Chong-xian , Carvajal-Carmona Luis G. , Welm Alana L. , Welm Bryan E. , Govindan Ramaswamy , Li Shunqiang , Davies Michael A. , Roth Jack A. , Meric-Bernstam Funda , Xie Yang , Herlyn Meenhard , Ding Li , Lewis Michael T. , Bult Carol J. , Dean Dennis A. , Chuang Jeffrey H.
Published: September 2024

Figure S5
Figure S12 from A Pan-Cancer Patient-Derived Xenograft Histology Image Repository with Genomic and Pathologic Annotations Enables Deep Learning Analysis
Authors: White Brian S. , Woo Xing Yi , Koc Soner , Sheridan Todd , Neuhauser Steven B. , Wang Shidan , Evrard Yvonne A. , Chen Li , Foroughi pour Ali , Landua John D. , Mashl R. Jay , Davies Sherri R. , Fang Bingliang , Raso Maria Gabriela , Evans Kurt W. , Bailey Matthew H. , Chen Yeqing , Xiao Min , Rubinstein Jill C. , Sanderson Brian J. , Lloyd Michael W. , Domanskyi Sergii , Dobrolecki Lacey E. , Fujita Maihi , Fujimoto Junya , Xiao Guanghua , Fields Ryan C. , Mudd Jacqueline L. , Xu Xiaowei , Hollingshead Melinda G. , Jiwani Shahanawaz , Acevedo Saul , Davis-Dusenbery Brandi N. , Robinson Peter N. , Moscow Jeffrey A. , Doroshow James H. , Mitsiades Nicholas , Kaochar Salma , Pan Chong-xian , Carvajal-Carmona Luis G. , Welm Alana L. , Welm Bryan E. , Govindan Ramaswamy , Li Shunqiang , Davies Michael A. , Roth Jack A. , Meric-Bernstam Funda , Xie Yang , Herlyn Meenhard , Ding Li , Lewis Michael T. , Bult Carol J. , Dean Dennis A. , Chuang Jeffrey H.
Published: September 2024

Figure S12
Targeting the Synthetic Lethal Relationship between FOCAD and TUT7 Represents a Potential Therapeutic Opportunity for TUT4/7 Small-Molecule Inhibitors in Cancer
Authors: Triboulet Robinson , Sadykov Khikmet , Harvey Darren M. , Wilson David M. , Steinbaugh Michael J. , Mayo Christopher B. , Hawley Dillon , Madanjian Andrew , Fyfe Corey , Bracken Christina , Rivera-Rivera Izarys , Ericsson Anna , Snyder Andrew R. , Knutson Sarah K. , Stein Ross L. , Gibaja Veronica , Ghosh Shomir , Campbell Robert M.
Published: September 2024

Targeting synthetic lethal interactions among genes has emerged as a promising strategy for cancer therapy. This study explores the intricate interplay among terminal uridylyltransferase 4 (TUT4) and terminal uridylyltransferase 7 (TUT7), the 3′-5′ exoribonuclease DIS3L2, and the superkiller (SKI) complex–interacting factor focadhesin (FOCAD) in the context of cancer vulnerability. Using CRISPR and public functional genomics data, we show impairment of cell proliferation upon knockout of TUT7 or DIS3L2, but not TUT4, on cancer cells with FOCAD loss. Moreover, we report the characterization of the first potent and selective TUT4/7 inhibitors that substantially reduce uridylation and demonstrate in vitro and in vivo antiproliferative activity specifically in FOCAD-deleted cancer. FOCAD deficiency posttranscriptionally disrupts the stability of the SKI complex, whose role is to safeguard cells against aberrant RNA. Reintroduction of FOCAD restores the SKI complex and makes these cells less sensitive to TUT4/7 inhibitors, indicating that TUT7 dependency is driven by FOCAD loss. We propose a model in which, in the absence of FOCAD, TUT7 and DIS3L2 function as a salvage mechanism that degrades aberrant RNA, and genetic or pharmacologic inhibition of this pathway leads to cell death. Our findings underscore the significance of FOCAD loss as a genetic driver of TUT7 vulnerability and provide insights into the potential utility of TUT4/7 inhibitors for cancer treatment.
Abstract A015 FGF8 promotes non-canonical KRAS/MAPK pathway in favorable histology Wilms' tumor
Authors: Su Yongdong , Skinner Katie T. , Cooper Garrett W. , Kang Sumin , Yin Hong , Yustein Jason T. , Hong Andrew L.
Published: September 2024

Favorable Histology Wilms tumor (FHWT) is the most common pediatric kidney cancer and those with relapsed FHWT continue to have poor prognoses. A challenge in the field of FHWT research is the lack of faithful preclinical in vitro models for both primary and relapsed tumors. This prevents us from understanding the biology of FHWT and introducing new targeted therapies into FHWT clinical trials. We recently established 10 FHWT cell lines, including one from a relapsed case, which faithfully recapitulated the genome and transcriptome of the primary tumor. However, challenges persist in maintaining the long-term growth of these cell lines, limiting our insight into the functional study of FHWT. Through comparison of the transcriptome of the FHWT primary tumor samples to their respective cell lines, we identified upregulation of fibroblast growth factor 8 (FGF8) expression in primary tumors. We then performed functional genomics to study the role of FGF8 in FHWT. We found that the splice variants, FGF8b or FGF8f, are required for the maintenance of FHWT cells. Re-introducing these two splice variants using either exogenous addition or endogenous overexpression led to increased viability and passaging of FHWT cell line models by an average of 100% and 30%, respectively. Further, we found that overexpressing FGF8b or FGF8f led to increased clonogenicity and invasion in vitro and led to tumor formation in vivo. Our mechanistic studies suggest that FGF8 drives a stemness and proliferation program through a non-canonical KRAS/MAPK pathway: FGF8b and FGF8f overexpression activates MEK1/2 without activating Erk1/2 while still promoting ETV1 and ETV4, leading to increased cell proliferation. Abrogation of MAPK pathway in vitro using MEK inhibitors led to decreased viability in cells overexpressing FGF8b and FGF8f. Together, our study highlights the oncogenic effect of FGF8 in FHWT and links FHWT to an unexpected non-canonical MAPK pathway.

Citation Format: Yongdong Su, Katie T. Skinner, Garrett W. Cooper, Sumin Kang, Hong Yin, Jason T. Yustein, Andrew L. Hong. FGF8 promotes non-canonical KRAS/MAPK pathway in favorable histology Wilms' tumor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A015.
Abstract A056 Intertumoral epigenetic heterogeneity in response to a novel therapy in Ewing sarcoma
Authors: Isenhart Emily , Gupta Ajay , Ohm Joyce
Published: September 2024

Like many pediatric cancers, Ewing sarcoma (EwS) is a genomically quiet disease. Driven by an oncogenic fusion protein, usually EWSR1-FLI1, the epigenome of this genetically homogenous cancer is a driver of clinical outcomes, where heightened epigenetic heterogeneity within tumors is associated with metastatic disease. While prognosis for localized disease is moderate, outcomes are dismal for patients who present with advanced, relapsed, or refractory disease and there is a lack of targeted therapies in this setting. We have previously described a targeted combination therapy harnessing DDK and WEE1 inhibition exploits elevated endogenous replication stress in EwS to force cells into mitotic catastrophe in vitro. While our experiments evaluating the efficacy of this combination in vivo have been extremely encouraging, the data have shown that individual mice receiving the same treatment have variable patterns of outgrowth after treatment cessation, with some mice demonstrating moderate increases in tumor volume and some mice demonstrating little to no tumor outgrowth. This differential response to therapy is most likely to occur through epigenetic dysregulation. Thus, we aim to interrogate intertumoral epigenetic heterogeneity and examine epigenetic profiles associated with treatment response using samples from in vivo studies. Samples were analyzed from a CDX model using TC32 cells injected subcutaneously. Reduced representation bisulfite sequencing was performed on a control arm (n = 5) and the following three treatment arms, where the DDK inhibitor is TAK-931 (simurosertib) and the WEE1 inhibitor is MK1775 (adavosertib): 1) Irinotecan + Temozolomide (n=9), 2) Irinotecan (full dose) + DDKi + WEE1i (n=7), 3) Irinotecan (half dose) + DDKi + WEE1i (n=9), for a total of 30 samples. Our analysis of this data evaluates epigenetic changes between treatment conditions and increases our understanding of epigenetic heterogeneity in EwS.

Citation Format: Emily Isenhart, Ajay Gupta, Joyce Ohm. Intertumoral epigenetic heterogeneity in response to a novel therapy in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A056.
Abstract A079 Mechanisms of chemotherapy resistance in rhabdomyosarcoma
Authors: Mathavarajah Sabateeshan , Wang Yueyang , Wei Yun , Antelo Diego , Langenau David M.
Published: September 2024

Background: Rhabdomyosarcoma (RMS) is a childhood cancer that originates from soft tissue and shares features with skeletal muscle. RMS patients are treated with a combination of radiation, surgical resection, and chemotherapy (VAC; vincristine, actinomycin D and cyclophosphamide). Unfortunately, 30% of patients eventually develop relapsed tumors due to resistance to VAC or radiation, of whom have an abysmal 17% five-year survival rate. To date, the mechanisms underlying resistance to VAC is poorly understood in RMS tumors, which are desperately needed for devising new therapeutic avenues to target VAC chemoresistance and improve the outcomes for these patients. Methods: We have recently generated long-term VAC-resistant RMS cell lines (from RD and Rh41 parental lines) to model chemoresistance. These cell lines were acclimated to high dose VAC over a 3-month period. Afterwards, single clones were isolated from these chemoresistant cell lines and assessed for upregulation of the PIK3CA/AKT/ABC transporter pathway by Western blot analysis. Results: We find that within the pool of resistant clones, there are two distinct pathways that are upregulated to promote VAC-resistance, one that elevates the PIK3CA/AKT/ABC transport pathway to rapidly efflux drugs from RMS cells. Astonishingly, this same drug resistance pathway is activated in both fusion-positive and fusion-negative RMS. The upregulated ABC transporters are well known drug efflux pumps and include ABCB1/MDR1, ABCC1/MRP1 and ABCG2/BCRP. We next show that the increased transcription of these ABC transporters occurs through an AKT-dependent mechanism – akin to that described by our group for an investigational chemotherapy that combines DNA damaging agent temozolomide with Olaparib PARP-inhibitor (OT). Using an inhibitor of PIK3CA signaling, Alpelisib, we show that we can resensitize these chemoresistant cell lines to VAC and OT. Conclusions: VAC-resistance occurs in part through PIK3CA/AKT signaling to promote drug efflux. The PIK3CA/AKT pathway can be therapeutically targeted to resensitize tumors to VAC. Future studies will focus on determining the mechanisms of drug resistance in tumors that fail to upregulate the PIK3CA/AKT/ABC transport pathway.

Citation Format: Sabateeshan Mathavarajah, Yueyang Wang, Yun Wei, Diego Antelo, David M. Langenau. Mechanisms of chemotherapy resistance in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A079.
Abstract B026: Infant ALL without KMT2A rearrangements harbor clinically relevant alterations and share common origins with childhood ALL
Authors: Zatzman Matthew , Seelisch Jennifer , Comitani Federico , Fuligni Fabio , Davidson Scott , Yuki Kyoko E. , Edwards Lisa-Monique , Brunga Ledia , Guest Erin , Hunger Stephen P. , Loh Mignon L. , Raetz Elizabeth A. , Chen John , Bartram Jack , Hitzler Johann K. , Brown Patrick A. , Gupta Sumit , Shlien Adam
Published: September 2024

Infant acute lymphoblastic leukemia (ALL) is characterized by high frequency of rearrangements in KMT2A (KMT2Ar), associated with poor outcomes. Infants lacking KMT2Ar typically have superior outcomes, but remain understudied. Here, we use whole genome and transcriptome sequencing to define driver mutations and transcriptional phenotypes in non-KMT2Ar infant ALL. Based on two index cases, we initially suspected that some infants with high-risk clinical features harbored clinically undetected non-canonical alterations to the KMT2A gene; however, we find no such evidence in our data. Instead, we find that these infants acquire other clinically relevant features such as Ph-like expression signatures, fusions impacting ZNF384, TCF3, ETV6::RUNX1, PAX5 or NUTM1, and events in known tumor genes such as CDKN2A, NOTCH1, and others. By mapping transcriptional profiles between infant and childhood B-ALL, we find that - in the absence of KMT2Ar - infant ALL resembles well defined childhood B-ALL subtypes, sharing the same genetic drivers. NUTM1 fusions are particularly enriched in infants compared to older children, and are associated with decreased MHC-Class II expression and B-cell developmental signaling pathways. Ph-like transcriptional signatures were apparent in several infants and confirmed by machine learning driven classification. Overall, our data support a common developmental origin of ALL without KMT2Ar in infants and children.

Citation Format: Matthew Zatzman, Jennifer Seelisch, Federico Comitani, Fabio Fuligni, Scott Davidson, Kyoko E. Yuki, Lisa-Monique Edwards, Ledia Brunga, Erin Guest, Stephen P. Hunger, Mignon L. Loh, Elizabeth A. Raetz, John Chen, Jack Bartram, Johann K. Hitzler, Patrick A. Brown, Sumit Gupta, Adam Shlien. Infant ALL without KMT2A rearrangements harbor clinically relevant alterations and share common origins with childhood ALL [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B026.
Spatially Resolved Whole-Transcriptomic and Proteomic Profiling of Lung Cancer and Its Immune Microenvironment According to PD-L1 Expression
Authors: Koh Jaemoon , Lee Dongjoo , Kim Sehui , Song Seung Geun , Han Bogyeong , Jeong Hyein , Kim Young A , Keam Bhumsuk , Lee Se-Hoon , Kim Kwangsoo , Jeon Yoon Kyung , Chung Doo Hyun
Published: September 2024

The expression of PD-L1 on tumor cells (TC) is used as an immunotherapy biomarker in lung cancer, but heterogeneous intratumoral expression is often observed. To better understand heterogeneity in the lung cancer tumor microenvironment, we performed proteomic and whole-transcriptomic digital spatial profiling analyses of TCs and immune cells (IC) in spatially matched areas based on tumor PD-L1 expression and the status of the immune microenvironment. We validated our findings using IHC, data from The Cancer Genome Atlas, and immunotherapy cohorts. ICs in areas with high PD-L1 expression on TCs showed more features, indicative of immunosuppression and exhaustion, than ICs in areas with low PD-L1 expression on TCs. TCs highly expressing PD-L1 within immune-inflamed areas showed upregulation of proinflammatory processes, whereas TCs highly expressing PD-L1 within immune-deficient areas showed upregulation of various metabolic processes. Using differentially expressed genes of TCs between the immune-inflamed and immune-deficient areas, we identified a prognostic gene signature for lung cancer. In addition, we found that a high ratio of CD8+ cells to M2 macrophages predicted favorable outcomes in patients with PD-L1–expressing lung cancer after immune checkpoint inhibitor therapy. Overall, this study demonstrates that TCs and ICs have distinct spatial features within the lung tumor microenvironment that are related to tumor PD-L1 expression and IC infiltration.
Supplementary Material SM2 from Inferring Characteristics of the Tumor Immune Microenvironment of Patients with HNSCC from Single-Cell Transcriptomics of Peripheral Blood
Authors: Cao Yingying , Chang Tiangen , Schischlik Fiorella , Wang Kun , Sinha Sanju , Hannenhalli Sridhar , Jiang Peng , Ruppin Eytan
Published: September 2024

Comprehensive lists of all signatures predicting patient ICB response.
Supplementary Figure 9 from Inferring Characteristics of the Tumor Immune Microenvironment of Patients with HNSCC from Single-Cell Transcriptomics of Peripheral Blood
Authors: Cao Yingying , Chang Tiangen , Schischlik Fiorella , Wang Kun , Sinha Sanju , Hannenhalli Sridhar , Jiang Peng , Ruppin Eytan
Published: September 2024

Supplementary Figure 9
Supplementary Figure 11 from Inferring Characteristics of the Tumor Immune Microenvironment of Patients with HNSCC from Single-Cell Transcriptomics of Peripheral Blood
Authors: Cao Yingying , Chang Tiangen , Schischlik Fiorella , Wang Kun , Sinha Sanju , Hannenhalli Sridhar , Jiang Peng , Ruppin Eytan
Published: September 2024

Supplementary Figure 11
Recurrence of Hepatocellular Carcinoma after Liver Transplantation: Clinical Patterns and Hierarchy of Salvage Treatments
Authors: Giuliani Tommaso , Montalvá Eva , Maupoey Javier , Boscá Andrea , Hernando Ana , Calatayud David , Navarro Vicente , Rubín Angel , Vinaixa Carmen , López-Andújar Rafael
Published: September 2024

Introduction: The multiparametric nature of recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) still leads to uncertainty with its practical management. This study aims to characterize the main posttransplant recurrence patterns of HCC and to explore the therapeutic modalities targeting recurrence. Methods: Consecutive patients who underwent LT for HCC at a single tertiary center were analyzed. The time from first recurrence to death was investigated for each site of presentation. The impact of each recurrence-targeted treatment on survival was studied. Results: Of 660 patients with HCC, any recurrence occurred in 96 (15.4%) patients with a median time to recurrence of 20.0 months (95% CI: 15.6–23.8). Patients recurred across different patters including solitary distant locations (30.8%, n = 28), liver only (24.2%, n = 22), lung (18.7%, n = 17), multi-organ disease (17.6%, n = 16), and bone (8.8%, n = 8). Multi-organ and bone recurrences had the poorest survival, while solitary distant lesions and pulmonary recurrences had the best outcomes. Each treatment modality carried a distinctive survival. Conclusions: Patients recurred across 3 patterns with different prognostic implications. The benefit of each treatment option on distinct recurrence patterns appears to be influenced by the biological behavior inherent in the recurrence pattern itself.
Negative Predictive Value of Single-Day Drug Provocation Test for Immediate and Non-Immediate Beta-Lactam Hypersensitivity Reactions in Children
Authors: Genis Cankat , Kuzucu Fatma Nur , Sengül Emeksiz Zeynep , Dibek Mısırlıoglu Emine
Published: September 2024

Introduction: Beta-lactam antibiotics (BLAs) commonly cause hypersensitivity reactions in children. These reactions are categorized into immediate reactions, which include urticaria, angioedema, bronchospasm, and anaphylaxis, and non-immediate reactions, such as maculopapular rashes and delayed-onset urticaria/angioedema. Rashes in children, often caused by infections, may be misdiagnosed as BLA allergy. However, over 90% tolerate the medication following an allergic evaluation. Methods: We aimed to evaluate patients with negative single-day drug provocation test (sdDPT) results for subsequent reactions and to determine the negative predictive value (NPV) of sdDPT for immediate (less than 1 h) and non-immediate (more than 1 h) suspected BLA allergy. In addition, non-immediate reactions were assessed by classifying them as occurring within 1–6 h or after 6 h. Patients who underwent sdDPT for suspected BLA allergy and tested negative between 2019 and 2023 were included in the study. They were questioned via telephone interviews about their reuse of the tested drug. Results: 404 patients who underwent sdDPT for suspected BLA allergy were evaluated. The NPV of BLA sdDPT was determined to be 97.3%. When patients were categorized based on the time interval between the last dose and the reaction, the NPV was 97% for those experiencing a reaction within the first hour of drug use and 96.7% for reactions occurring after more than 1 h. Non-immediate reactions were further evaluated, revealing an NPV of 98.7% for reactions occurring between 1 and 6 h, and 92.5% for reactions occurring after 6 h. Conclusion: Our findings demonstrate that sdDPT has a high NPV for both immediate and non-immediate reactions. However, the NPV of sdDPT was lower for reactions occurring more than 6 h after the last dose.
Impact of the COVID-19 Pandemic on Home Mechanical Ventilation in Germany: A Descriptive Observational Study
Authors: Stanzel Sarah Bettina , Wollsching-Strobel Maximilian , Majorski Daniel Sebastian , Kroppen Doreen , Berger Melanie Patricia , Schumacher Falk , Holle Johannes Fabian , Zimmermann Maximilian , Windisch Wolfram
Published: September 2024

Introduction: Over the last decade, the number of patients receiving home mechanical ventilation (HMV) has increased significantly, which has led to a limited availability of specialist centres, not least due to the scarcity of healthcare professionals. This situation was exacerbated by the COVID-19 pandemic. It is therefore assumed that the repurposing of resources has led to an aggravated change in the healthcare structure in HMV. Methods: This descriptive observational study analysed the Operation and Procedure Classification Codes for patients receiving HMV from 2008 to 2022. The data were provided by the Federal Statistical Office of Germany. Data were additionally analysed with respect to geographical distribution and ventilation status. Results: A total of 737,770 datasets were analysed (mean age in 2020: 66.5 years). There was a steady increase in HMV initiations (+6%) and controls (+9%) per year before the pandemic (2008–2019). Patient admissions during the pandemic revealed a 28% decrease, with the largest decrease in invasive ventilation (IV) follow-up visits (2019: 3,053; 2020: 2,199; −39%), while the number of IV initiations remained stable. There was a 19% decrease in the number of non-IV initiations in 2020 (16,919 vs. 14,227) and a 32% decrease in the number of follow-ups (45,812 vs. 34,813) in comparison with 2019. Conclusion: The pandemic has led to a significant decline of inpatient admissions for patients receiving HMV. This decline was most pronounced in the first year of the pandemic. Control visits in particular did not reach the pre-pandemic level. This is an indication of the ongoing change in the healthcare landscape as a result of the pandemic.
Diagnostic Workup of Retinal Vasculitis: An Algorithmic Approach
Authors: Arora Atul , Agarwal Manisha , Chieh Loh Nicholas , Amin Hind , Menia Nitin Kumar , Agrawal Rupesh , Gupta Vishali
Published: September 2024

Background: Retinal vasculitis has heterogeneous etiologies encompassing infections, autoimmune diseases, masquerades, and idiopathic causes. The heterogeneity in the underlying clinical features and etiologies of retinal vasculitis makes its diagnosis challenging for clinicians, the workup thus becomes quite extensive, and many a times several unwarranted investigations are done to look for a possible etiology. Summary: Timely and accurate diagnosis is crucial for effective management and vision preservation. The algorithmic approach needs understanding of the phenotype, clinical features, as well as imaging biomarkers so that only customized investigations are done in order to make the timely diagnosis and initiate specific therapy wherever required. Key Message: In this review article, we shall present an algorithmic approach that combines clinical assessment, ophthalmic imaging, laboratory investigations, and targeted ancillary tests.
A Novel Index Including Age, Sex, hTERT, and Methylated RUNX3 Is Useful for Diagnosing Early Gastric Cancer
Authors: Nakamura Katsuhiko , Suehiro Yutaka , Hamabe Koichi , Goto Atsushi , Hashimoto Shinichi , Kunimune Yuki , Ishiguro Akiyo , Okayama Naoko , Fujii Tomohiro , Nakahara Yukiko , Nishioka Mitsuaki , Higaki Shingo , Fujii Ikuei , Suzuki Chieko , Nishikawa Jun , Sakaida Isao , Takami Taro , Yamasaki Takahiro
Published: September 2024

Introduction: As the incidence of gastric cancer (GC) is increasing in East Asia including Japan, a simple blood test for early GC is needed as an alternative to upper gastrointestinal (UGI) endoscopy. We performed this study to address this issue. Methods: We collected serum samples from 319 participants comprising 225 healthy subjects without GC (control group) and 94 patients with early GC (early GC group). After evaluating copy numbers of serum hTERT and methylated RUNX3 (m-RUNX3) using the Combined Restriction Digital PCR (CORD) assay, which we developed, we assessed the diagnostic performance of hTERT and m-RUNX3 for early GC. Results: Serum levels of hTERT and m-RUNX3 were significantly higher in the early GC group than in the control group. The area under the curve (AUC) was 0.89 for hTERT and 0.78 for m-RUNX3. Multivariate logistic regression analysis revealed age, sex, hTERT copy number, and m-RUNX3 copy number to be independent factors for early GC. We then established a prediction formula and named it the ASTEm-R3 (age, sex, hTERT, and m-RUNX3) index. The AUC of the ASTEm-R3 index was 0.93 with a sensitivity of 79.7% and specificity of 91.1%. Conclusion: We demonstrated excellent performance of the ASTEm-R3 index using the CORD assay to detect early GC. This index might be a promising alternative to UGI endoscopy.
Meta-Analysis of the Efficacy and Safety of Radiofrequency Catheter Ablation for Pediatric Paroxysmal Supraventricular Tachycardia
Authors: Zhang Xue , Yuan Yue
Published: September 2024

Introduction: This meta-analysis was to evaluate the efficacy and safety of radiofrequency catheter ablation (RFCA) in treating children with paroxysmal supraventricular tachycardia (PSVT). Methods: From inception to December 16, 2023, PubMed, Embase, Cochrane Library, Web of Science, CNKI (China National Knowledge Infrastructure), VIP (Chinese Science and Technology Periodical Database), and WanFang were searched for this meta-analysis. Children under the age of 18 diagnosed with atrioventricular reentrant tachycardia (AVRT) and atrioventricular nodal reentrant tachycardia (AVNRT) were enrolled. The outcomes included the success rate of RFCA, the recurrence rate of PSVT following RFCA treatment, and any complications associated with the procedure. Newcastle-Ottawa Scale (NOS) was used to assess the quality of studies. The outcome data were represented as rates (RATE) and corresponding 95% confidence intervals (CIs). Subgroup analyses were conducted based on regions and follow-ups. Results: Fourteen articles encompassing 6,032 children were included in the study. RFCA demonstrated remarkable efficacy in children patients, achieving success rates of 98% (RATE: 0.98, 95% CI: 0.96–0.99) for AVRT and 99% (RATE: 0.99, 95% CI: 0.98–1.00) for AVNRT. The analysis also reveals that post-RFCA, the recurrence rates for AVRT were 5% (RATE: 0.05, 95% CI: 0.03–0.07), while for AVNRT, they were slightly lower at 4% (RATE: 0.04, 95% CI: 0.02–0.08). In the subset of Asian children patients, these recurrence rates were observed to be 5% for AVRT and 3% for AVNRT. Monitoring for a duration of up to 12 months of post-RFCA indicated recurrence rates of 4% for AVRT and 3% for AVNRT. However, for follow-up periods extending beyond 1 year, there was a slight increase in these rates to 4% for AVRT and 6% for AVNRT. Additionally, the complication rates associated with RFCA in the children population were relatively minimal, recorded at 2% (RATE: 0.02, 95% CI: −0.01–0.06) for AVRT and 1% (RATE: 0.01, 95% CI: 0.00–0.02) for AVNRT. Conclusion: RFCA appears to be a highly effective and safe treatment option for AVRT and AVNRT in children, with high success rates and relatively low recurrence and complication rates. However, long-term follow-up may be necessary to monitor for potential recurrences. These findings are valuable for clinicians and patients in making informed decisions about the treatment of these cardiac arrhythmias in pediatric patients.
Disruption of Lipid Profile, Glucose Metabolism, and Leptin Levels following Citalopram Administration and High-Carbohydrate and High-Cholesterol Diet in Mice
Authors: Hammer Tomáš , Kotolová Hana , Procházka Jiří , Karpíšek Michal
Published: September 2024

Introduction: Depression therapy has been linked to negative effects on energy metabolism, which can be attributed to various factors, including an ongoing inflammatory process commonly seen in metabolic disorders. Unhealthy lifestyle choices of patients and the impact of antidepressants on body weight and lipid and glucose metabolism also contribute to these metabolic side effects. Although not as pronounced as other psychopharmaceuticals, the increasing use of antidepressants raises concerns about their potential impact on public health. The study aimed to evaluate the short- and long-term effects of the antidepressant citalopram and its long-term combination with a special diet on metabolic parameters in mice. Methods: Animals were randomly divided into 5 groups – control, control + special diet, citalopram (10 mg/kg for 35 days), citalopram + special diet (10 mg/kg for 35 days), and citalopram (10 mg/kg for 7 days). After a described time of administration, animals were anesthetized, blood and fat and liver tissues were collected. Biochemical parameters of lipid metabolism (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides) and glucose were analyzed using spectrophotometry and relevant adipokines and cytokines were evaluated by ELISA. Results: After a week of application of citalopram, we observed dyslipidemia that persisted even at the end of the 5-week experiment. Furthermore, after 5 weeks of citalopram administration, we observed a significant decrease in body weight gain and decreased leptin levels. Changes in lipid metabolism, higher levels of adipokines leptin and PAI-1 were observed due to the special diet after 5 weeks. Conclusions: Our research suggests that the effects of citalopram and a diet on the metabolism of mice can be significant, both in the short term (1 week) and in the long term (5 weeks).
Utility of Pipet Curet Cytology and Biopsy as a Diagnostic Method for Endometrial Endometrioid Carcinoma
Authors: Kurata Makiko , Tajiri Takuma , Ueda Masataka , Inomoto Chie , Sugiyama Tomoko , Fujita Hirotaka , Nomura Nozomi , Machida Tomohisa , Iida Tetsuji , Ooiwa Ippei , Nishijima Yoshihiro , Kajiwara Hiroshi , Muramatsu Toshinari , Nakamura Naoya
Published: September 2024

Introduction: We aimed to determine the utility of Pipet Curet cytology (PCC) and Pipet Curet biopsy (PCB) for diagnosing uterine endometrial endometrioid carcinoma (EEC). Methods: We divided 77 patients with EEC into two groups per Federation of Gynecology and Obstetrics (FIGO) grades: G1 (n = 44) and G2/3 (n = 33) and compared the diagnostic sensitivity of PCC, PCB, and PCC and PCB combined, retrospectively. Next, we investigated any diagnostic discordance between PCC-based and PCB-based diagnoses per FIGO grade group. Results: The diagnostic sensitivity of PCC, PCB, and the two modalities combined was significantly higher for G2/3 EECs than for G1 EECs (72.7% vs. 45.5%, p = 0.0209; 84.8% vs. 63.6%, p = 0.0434; and 93.9% vs. 65.9%, p = 0.0046, respectively), likely due to more friable cancer cells in higher grade EEC cases. Among our 77 EEC patients, there were 4 patients (5.19%) with PCC-based concordant but PCB-based discordant results against EEC, in the G2/3 group predominantly. Diagnostic sensitivity of all cases increased from 72.7% (56/77) by PCB alone to 77.9% (60/77) by use of both modalities combined. Conclusion: Cytologic evaluation can reduce the number of false-negative histologic diagnoses. By providing complementary information, the two modalities combined from the Pipet Curet procedure would be valuable as a diagnostic method for EEC.
Spatial Transcriptomic Approach to Understanding Coronary Atherosclerotic Plaque Stability
Authors: Gastanadui Maria G. , Margaroli Camilla , Litovsky Silvio , Richter Robert P. , Wang Dezhi , Xing Dongqi , Wells J. Michael , Gaggar Amit , Nanda Vivek , Patel Rakesh P. , Payne Gregory A.
Published: September 2024

BACKGROUND:

Coronary atherosclerotic plaques susceptible to acute coronary syndrome have traditionally been characterized by their surrounding cellular architecture. However, with the advent of intravascular imaging, novel mechanisms of coronary thrombosis have emerged, challenging our contemporary understanding of acute coronary syndrome. These intriguing findings underscore the necessity for a precise molecular definition of plaque stability. Considering this, our study aimed to investigate the vascular microenvironment in patients with stable and unstable plaques using spatial transcriptomics.

METHODS:

Autopsy-derived coronary arteries were preserved and categorized by plaque stability (n=5 patients per group). We utilized the GeoMx spatial profiling platform and Whole Transcriptome Atlas to link crucial histological morphology markers in coronary lesions with differential gene expression in specific regions of interest, thereby mapping the vascular transcriptome. This innovative approach allowed us to conduct cell morphological and spatially resolved transcriptional profiling of atherosclerotic plaques while preserving crucial intercellular signaling.

RESULTS:

We observed intriguing spatial and cell-specific transcriptional patterns in stable and unstable atherosclerotic plaques, showcasing regional variations within the intima and media. These regions exhibited differential expression of proinflammatory molecules (eg, IFN-γ [interferon-γ], MHC [major histocompatibility complex] class II, proinflammatory cytokines) and prothrombotic signaling pathways. By using lineage tracing through spatial deconvolution of intimal CD68
+
(cluster of differentiation 68) cells, we characterized unique, intraplaque subpopulations originating from endothelial, smooth muscle, and myeloid lineages with distinct regional locations associated with plaque instability. In addition, unique transcriptional signatures were observed in vascular smooth muscle and CD68
+
cells among plaques exhibiting coronary calcification.

CONCLUSIONS:

Our study illuminates distinct cell-specific and regional transcriptional alterations present in unstable plaques. Furthermore, we characterize spatially resolved, in situ evidence supporting cellular transdifferentiation and intraplaque plasticity as significant contributors to plaque instability in human coronary atherosclerosis. Our results provide a powerful resource for the identification of novel mediators of acute coronary syndrome, opening new avenues for preventative and therapeutic treatments.