bluuebunny/crossref_metadata_2025 huggingface dataset:
HDFCN: A Robust Hybrid Deep Network Based on Feature Concatenation for Cervical Cancer Diagnosis on WSI Pap Smear Slides
Authors: Chauhan Nitin Kumar , Singh Krishna , Kumar Amit , Kolambakar Swapnil Baburav
Published: April 2023

Cervical cancer is a critical imperilment to a female’s health due to its malignancy and fatality rate. The disease can be thoroughly cured by locating and treating the infected tissues in the preliminary phase. The traditional practice for screening cervical cancer is the examination of cervix tissues using the Papanicolaou (Pap) test. Manual inspection of pap smears involves false‐negative outcomes due to human error even in the presence of the infected sample. Automated computer vision diagnosis revamps this obstacle and plays a substantial role in screening abnormal tissues affected due to cervical cancer. Here, in this paper, we propose a hybrid deep feature concatenated network (HDFCN) following two‐step data augmentation to detect cervical cancer for binary and multiclass classification on the Pap smear images. This network carries out the classification of malignant samples for whole slide images (WSI) of the openly accessible SIPaKMeD database by utilizing the concatenation of features extracted from the fine‐tuning of the deep learning (DL) models, namely, VGG‐16, ResNet‐152, and DenseNet‐169, pretrained on the ImageNet dataset. The performance outcomes of the proposed model are compared with the individual performances of the aforementioned DL networks using transfer learning (TL). Our proposed model achieved an accuracy of 97.45% and 99.29% for 5‐class and 2‐class classifications, respectively. Additionally, the experiment is performed to classify liquid‐based cytology (LBC) WSI data containing pap smear images.
A Novel FRBF‐Type Model for Nonlinear Time Series Prediction
Authors: Xu Wenquan , Hu Hui
Published: April 2023

Accurate prediction of time series is complex due to nonlinear characteristics but can play a significant role in practical problem. In this paper, a novel varying‐coefficient hybrid model is proposed to accurately predict the nonlinear time series. A set of fuzzy radial basis function (FRBF) neural networks is used to approximate the varying functional coefficients of the state‐dependent autoregressive model with exogenous variables (SD‐ARX). The obtained model is called the fuzzy radial basis function network‐based autoregressive model with exogenous variables (FRBF‐ARX), which combines the advantages of the FRBF in function approximation and the SD‐ARX model in nonlinear dynamics description. Then, a structured nonlinear parameter optimization method (SNPOM) and the modified multifold cross‐validation criterion are used to estimate the parameters of the proposed varying‐coefficient FRBF‐ARX model. The performances of the FRBF‐ARX model are used to predict the PM2.5 concentration and simulated SISO nonlinear process, respectively, and the performances of the proposed model are also compared and discussed. The experimental results show that the FRBF‐ARX model has better performances of accuracy on nonlinear time series forecasting than that of other models.
Evaluation of the Wound Healing Potential of Cynara humilis Extracts in the Treatment of Skin Burns
Authors: Salhi Najoua , El Guourrami Otman , Rouas Lamiae , Moussaid Siham , Moutawalli Amina , Benkhouili Fatima Zahra , Ameggouz Mouna , Alshahrani Mohammed Merae , Al Awadh Ahmed Abdullah , Bouyahya Abdelhakim , Faouzi My El Abbes , Cherrah Yahya
Published: April 2023

Cynara humilis is traditionally used to treat skin burns and microbial infections. However, experimental studies on this plant are rare. Furthermore, the aim of this study was to investigate the effects of Cynara humilis, a Moroccan herbal remedy, on the healing of deep second‐degree burns in rats with a silver sulfadiazine group. This research was also carried out to confirm if C. humilis had antibacterial capabilities. Under typical burn procedures, each rat received a deep second‐degree burn on the upper back. The burns were treated regularly with control groups (control and control VH), silver sulfadiazine (SDD) in group 3, C. humilis ethanolic extract (CHEE) in group 4, and C. humilis aqueous extract (CHAE) in group 5. Throughout the treatment, digital photography was used to measure rat responses to the treatment until day 18. After the scar biopsy at the end of the study, histological parameters (inflammatory cells, collagen, epithelialization, fibrosis, and granulation tissue) were assessed. Using the well technique, the antibacterial activity of the extracts was tested against Staphylococcus aureus CIP 483, Bacillus subtilis CIP 5262, Escherichia coli CIP 53126, Pseudomonas aeruginosa CIP 82118, and Salmonella enterica CIP 8039, and the results showed important activities of the ethanolic and aqueous extracts against the five species tested with MICs of 2 and 4 mg/mL, respectively. In the aqueous extract group, the wound healed faster. In addition, the healing rate in the C. humilis extracts (CHEA and CHEE) group was faster than in the silver sulfadiazine and control groups. In the C. humilis group, maximum wound surface recovery was observed at the same time, as it was not noted in the silver sulfadiazine group. Pathologically, epithelialization was more marked in wounds treated with C. humilis extracts (CHE). Angiogenesis and inflammatory cells were considerably lower in the CHE group than in the silver and other control groups. However, elastic fibers were considerable in the CHE‐treated group. In histological examination, the C. humilis group had a low incidence of angiogenesis and inflammation, indicating that this group had less wound scarring. Collagen and burn wound healing were both faster in the C. humilis group. The findings of this study suggest that C. humilis, as indicated by traditional medicine, is a promising natural source for the management of wound healing.
Black and Yellow Soybean Consumption Prevents High‐Fat Diet‐Induced Obesity by Regulating Lipid Metabolism in C57BL/6 Mice
Authors: Jeong Eun Woo , Dhungana Sanjeev Kumar , Yang Yun Sun , Baek Youjin , Seo Jeong-Hyun , Kang Beom-Kyu , Jung Chan-Sik , Han Sang-Ik , Lee Hyeon Gyu
Published: April 2023

To evaluate the antiobesity effects of yellow and black soybean, C57BL/6 mice were provided with a normal diet, high‐fat diet, HFD‐containing yellow soybean powder (YS), and black soybean powder (BS) for six weeks. Compared with the HFD group, both YS and BS decreased body weight by 30.1% and 37.2% and fat in tissue by 33.3% and 55.8%, respectively. Simultaneously, both soybeans significantly reduced the serum triglyceride and total cholesterol levels and regulated the lipogenic mRNA expressions of Pparγ, Acc, and Fas genes in the liver, supporting reduced body adiposity. Furthermore, BS significantly increased Pgc‐1α and Ucp1 mRNA expression levels in epididymal adipose tissue, indicating thermogenesis is the key mechanism of BS. Taken together, our findings suggest that both soybeans prevent high‐fat diet‐induced obesity in mice by regulating lipid metabolism, and BS, in particular, has a greater antiobesity potential than YS.
Regulatory Effect of Inflammatory Mediators in Intervertebral Disc Degeneration
Authors: Li Zhangfu , Yang Honghao , Hai Yong , Cheng Yunzhong
Published: April 2023

Intervertebral disc degeneration (IDD) is a major contributor to back, neck, and radicular pain. It is related to changes in tissue structure and function, including the breakdown of the extracellular matrix (ECM), aging, apoptosis of the nucleus pulposus, and biomechanical tissue impairment. Recently, an increasing number of studies have demonstrated that inflammatory mediators play a crucial role in IDD, and they are being explored as potential treatment targets for IDD and associated disorders. For example, interleukins (IL), tumour necrosis factor-α (TNF-α), chemokines, and inflammasomes have all been linked to the pathophysiology of IDD. These inflammatory mediators are found in high concentrations in intervertebral disc (IVD) tissues and cells and are associated with the severity of LBP and IDD. It is feasible to reduce the production of these proinflammatory mediators and develop a novel therapy for IDD, which will be a hotspot of future research. In this review, the effects of inflammatory mediators in IDD were described.
Applicability of Darbo’s Fixed Point Theorem on the Existence of a Solution to Fractional Differential Equations of Sequential Type
Authors: Awadalla Muath , Abuasbeh Kinda , Manigandan Murugesan , Al Ghafli Ahmed A. , Al Salman Hassan J.
Published: April 2023

In this article, we study the existence of the solution for the fractional differential equations of sequential type with nonlocal integral boundary conditions. The main results are established with the aid of Darbo’s fixed point theorem and Hausdorff’s measure of noncompactness method. The stability of the proposed fractional differential equation is also investigated via the Ulam–Hyer technique. In addition, an applied example that supports the theoretical results reached through this study is included.
Microstructure and Mechanical Properties of Gradient Nanostructured Q345 Steel Prepared by Ultrasonic Severe Surface Rolling
Authors: Ge Chao , Meng Weilong , Feng Handui , Cui Muchun , Dong Lei , Miao Tianfeng , Huo Yantong , Wu Jiemin , Han Jing
Published: April 2023

In this work, ultrasonic severe surface rolling (USSR), a new surface nanocrystallization technique, is used to prepare gradient nanostructure (GNS) on the commercial Q345 structural steel. The microstructure of the GNS surface layer is characterized by employing EBSD and TEM, and the result indicates that a nanoscale substructure is formed at the topmost surface layer. The substructures are composed of subgrains and dislocation cells and have an average size of 309.4 nm. The GNS surface layer after USSR processing for one pass has a thickness of approximately 300 μm. The uniaxial tensile measurement indicates that the yield strength of the USSR sample improves by 25.1% compared to the as-received sample with slightly decreased ductility. The nanoscale substructure, refined grains, high density of dislocations, and hetero-deformation-induced strengthening are identified as responsible for the enhanced strength. This study provides a feasible approach to improving the mechanical properties of structural steel for wide applications.
Association of Kinase‐Insert‐Domain‐Containing Receptor Polymorphisms with Glioma Susceptibility in a Chinese Population: A Hospital‐Based Case‐Control Study
Authors: Huang Zhi-Fa , Zhu Wei , Wang Chen , Mo Li-Dong , Huang Hui-Ling , Tong Xiao-Guang
Published: April 2023

Background. Gliomas are the most common malignant tumors of the central nervous system. However, the inherited genetic variation in gliomas is presently unclear. Therefore, this study investigated the association of the rs2071559 and rs2239702 gene polymorphisms with glioma susceptibility in Chinese patients. Methods. In this study, a case‐control approach was used to compare and analyze whether two genes, rs2071559 and rs2239702, were associated with the risk of glioma formation. Results. The cases and controls were matched for sex, smoking status, and family history of cancer using single nucleotide polymorphisms. Specific rs2071559 and rs2239702 alleles were found much more frequently in the glioma group than in the control group (P < 0.001 and P = 0.014, respectively). Conclusions. These findings suggest that specific rs2071559 and rs2239702 polymorphisms are associated with a higher risk of glioma development; the risk allele is C in rs2071559 or A in rs2239702. Moreover, the kinase‐insert‐domain‐containing receptor may act as a suppressor of tumor progression.
HHV-6 Meningoencephalitis in a Healthy Adult Female
Authors: Valentini Nicholas , Chen Cynthia
Published: April 2023

Introduction. We describe the case of a 47-year-old female who presented to an academic tertiary emergency department with two to three days of worsening fever, headache, malaise, and rigors. A broad infectious workup revealed a diagnosis of Human Herpesvirus 6 (HHV-6) meningoencephalitis without any additional identifiable causes. HHV-6, the virus responsible for the childhood disease roseola, is a common cause of fever, seizures, diarrhea, and a characteristic faint-pink rash in children. Symptomatic HHV-6 infection in adults is far less common. We believe this represents one of only a few reported cases of HHV-6 meningoencephalitis in an immunocompetent host. Case Report. A 47-year-old female presented to the emergency department with two to three days of fever, headache, malaise, and rigors. She had a noncontributory medical, surgical, and family history but had traveled extensively in northeast Africa six months prior. A physical exam was notable for a wide based gait, photophobia, mild nuchal rigidity, and pain with active range of motion of the neck. A broad infectious workup was pursued; however, given headache, fever, and subjective nuchal rigidity, the highest concern was for meningoencephalitis. A lumbar puncture was positive for HHV-6 without any other diagnostic findings to otherwise explain the patient’s symptoms. The patient was discharged on hospital day 3 with improving symptoms. Conclusion. HHV-6 meningoencephalitis has previously been described as a pathogen associated with individuals with immunosuppressive conditions. There have been several prior case reports of symptomatic meningoencephalitis in immune-competent individuals, and we believe this case adds to a growing body of evidence that HHV-6 meningoencephalitis can cause symptomatic infection in a broader patient population.
Successful Treatment of Respiratory Failure in a Patient with Prader-Willi Syndrome with Noninvasive Ventilation with AVAPS
Authors: Hwig Nauras , Diaz-Abad Montserrat , Peng Victor T. , So Jennifer Y. , Lasso-Pirot Anayansi
Published: April 2023

Prader-Willi syndrome (PWS) is the most prevalent syndromic form of obesity, which starts during early childhood in the setting of hyperphagia. Due to the development of obesity, there is a high prevalence of obstructive sleep apnea (OSA) among these patients. This case report presents a patient with PWS with morbid obesity, severe OSA, and obesity hypoventilation syndrome admitted to the hospital for hypoxemic and hypercapnic respiratory failure. Noninvasive ventilation (NIV) with average volume-assured pressure support, a newer NIV modality, was used successfully to treat this patient, achieving major clinical and gas exchange improvement both during the hospitalization and long term after discharge.
Supplementary Table 4 from Prevalence and Prognostic Significance of Malnutrition in Patients with Brain Metastasis
Authors: Liu Zheran , Zhang Yu , Pei Yiyan , He Yan , Yu Jiayi , Zhang Renjie , Wang Jingjing , Chong Weelic , Hai Yang , Peng Xingchen , Fang Fang
Published: April 2023

Supplementary Table 4 The results of multivariate Cox analyses of CONUT (A), PNI (B), and NRI (C) scores with overall survival in patients with brain metastases.
Supplementary Table 3 from Prevalence and Prognostic Significance of Malnutrition in Patients with Brain Metastasis
Authors: Liu Zheran , Zhang Yu , Pei Yiyan , He Yan , Yu Jiayi , Zhang Renjie , Wang Jingjing , Chong Weelic , Hai Yang , Peng Xingchen , Fang Fang
Published: April 2023

Supplementary Table 3. Patients' malnutrition status stratified by BMI groups.
Supplementary Figure 6 from Prevalence and Prognostic Significance of Malnutrition in Patients with Brain Metastasis
Authors: Liu Zheran , Zhang Yu , Pei Yiyan , He Yan , Yu Jiayi , Zhang Renjie , Wang Jingjing , Chong Weelic , Hai Yang , Peng Xingchen , Fang Fang
Published: April 2023

Supplementary Figure 6 Kaplan-Meier curves for overall survival in patients who received chemotherapy and radiotherapy.
Supplementary Figure 5 from Prevalence and Prognostic Significance of Malnutrition in Patients with Brain Metastasis
Authors: Liu Zheran , Zhang Yu , Pei Yiyan , He Yan , Yu Jiayi , Zhang Renjie , Wang Jingjing , Chong Weelic , Hai Yang , Peng Xingchen , Fang Fang
Published: April 2023

Supplementary Figure 5. Time-dependent ROC curves of malnutrition scores.
Prevalence and Prognostic Significance of Malnutrition in Patients with Brain Metastasis
Authors: Liu Zheran , Zhang Yu , Pei Yiyan , He Yan , Yu Jiayi , Zhang Renjie , Wang Jingjing , Chong Weelic , Hai Yang , Peng Xingchen , Fang Fang
Published: April 2023

Background:

Malnutrition is a severe but modifiable risk factor for cancers. However, the relationship between malnutrition and the survival of patients with brain metastases has not been fully revealed. We aimed to evaluate the prevalence of malnutrition and assess its prognostic value on patients with brain metastases

Methods:

We retrospectively recruited 2,633 patients with brain metastases between January 2014 and September 2020. Three malnutrition scores were used to evaluate patients’ malnutrition status at their first admission, including controlling nutritional status, the nutritional risk index, and the prognostic nutritional index. The association between malnutrition and overall survival (OS) was estimated.

Results:

The three malnutrition scores were associated with each other and with body mass index (BMI). Malnutrition assessed by any of the three scores was significantly associated with poor OS. All three malnutrition scores were better indicators than BMI, and adding malnutrition scores to the Graded Prognostic Assessment (GPA) scoring system could significantly improve the accuracy of prognosis prediction.

Conclusions:

Malnutrition monitoring using any of the three malnutrition scores on patients’ first admission could be a better survival indicator for patients with brain metastases compared with BMI alone.

Impact:

Malnutrition is a more significant indicator of survival stratification compared with BMI. Adding malnutrition to the GPA score system achieves better survival prediction.
Supplemental Table 2 from Multicenter Phase I Trial of Ivosidenib as Maintenance Treatment Following Allogeneic Hematopoietic Cell Transplantation for IDH1-Mutated Acute Myeloid Leukemia
Authors: Fathi Amir T. , Kim Haesook T. , Soiffer Robert J. , Levis Mark J. , Li Shuli , Kim Annette S. , DeFilipp Zachariah , El-Jawahri Areej , McAfee Steve L. , Brunner Andrew M. , Amrein Philip C. , Mims Alice S. , Knight Laura W. , Kelley Devon , Bottoms AJ S. , Perry Lindsey H. , Wahl Jonathan L. , Brock Jennifer , Breton Elayne , Marchione Dylan M. , Ho Vincent T. , Chen Yi-Bin
Published: April 2023

Marrow IDH1 VAF prior to Transplant and Maintenance
Supplementary Figure S8 from Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer
Authors: Tolmeijer Sofie H. , Boerrigter Emmy , Sumiyoshi Takayuki , Kwan Edmond M. , Ng Sarah W.S. , Annala Matti , Donnellan Gráinne , Herberts Cameron , Benoist Guillemette E. , Hamberg Paul , Somford Diederik M. , van Oort Inge M. , Schalken Jack A. , Mehra Niven , van Erp Nielka P. , Wyatt Alexander W.
Published: April 2023

Baseline circulating tumor DNA fraction according to detection status at 4 weeks
Supplementary Figure S7 from Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer
Authors: Tolmeijer Sofie H. , Boerrigter Emmy , Sumiyoshi Takayuki , Kwan Edmond M. , Ng Sarah W.S. , Annala Matti , Donnellan Gráinne , Herberts Cameron , Benoist Guillemette E. , Hamberg Paul , Somford Diederik M. , van Oort Inge M. , Schalken Jack A. , Mehra Niven , van Erp Nielka P. , Wyatt Alexander W.
Published: April 2023

On-treatment ctDNA fraction, PSA responses and baseline genomic and clinical features
Supplementary Figure S5 from Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer
Authors: Tolmeijer Sofie H. , Boerrigter Emmy , Sumiyoshi Takayuki , Kwan Edmond M. , Ng Sarah W.S. , Annala Matti , Donnellan Gráinne , Herberts Cameron , Benoist Guillemette E. , Hamberg Paul , Somford Diederik M. , van Oort Inge M. , Schalken Jack A. , Mehra Niven , van Erp Nielka P. , Wyatt Alexander W.
Published: April 2023

Relationship between baseline circulating tumor DNA fraction and patient outcomes
Supplementary Figure S10 from Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer
Authors: Tolmeijer Sofie H. , Boerrigter Emmy , Sumiyoshi Takayuki , Kwan Edmond M. , Ng Sarah W.S. , Annala Matti , Donnellan Gráinne , Herberts Cameron , Benoist Guillemette E. , Hamberg Paul , Somford Diederik M. , van Oort Inge M. , Schalken Jack A. , Mehra Niven , van Erp Nielka P. , Wyatt Alexander W.
Published: April 2023

Changes in ctDNA fraction and PSA levels between baseline and 4 weeks on-treatment in relation to the durability of response
Supplementary Figure S2 from Efficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations
Authors: Grant Michael J. , Aredo Jacqueline V. , Starrett Jacqueline H. , Stockhammer Paul , van Alderwerelt van Rosenburgh Iris K. , Wurtz Anna , Piper-Valillo Andrew J. , Piotrowska Zofia , Falcon Christina , Yu Helena A. , Aggarwal Charu , Scholes Dylan , Patil Tejas , Nguyen Christina , Phadke Manali , Li Fang-Yong , Neal Joel , Lemmon Mark A. , Walther Zenta , Politi Katerina , Goldberg Sarah B.
Published: April 2023

Supplementary Figure S2. Progression Free Survival for patients with tumors harboring select exon 19 deletions treated with first-line osimertinib. The point estimate for median progression free survival associated with each mutation is listed to the right of the figure legend.
Supplementary Table S1 from G-CSF Is a Novel Mediator of T-Cell Suppression and an Immunotherapeutic Target for Women with Colon Cancer
Authors: Ray Anita L. , Saunders Apryl S. , Nofchissey Robert A. , Reidy Megan A. , Kamal Maria , Lerner Megan R. , Fung Kar-Ming , Lang Mark L. , Hanson Joshua A. , Guo Shaoxuan , Urdaneta-Perez Maria G. , Lewis Samara E. , Cloyde Michael , Morris Katherine T.
Published: April 2023

Supplementary Table 1: CyTOF antibody panel and source
Supplementary Data 3 from A Phase II Study of Epacadostat and Pembrolizumab in Patients with Advanced Sarcoma
Authors: Kelly Ciara M. , Qin Li-Xuan , Whiting Karissa A. , Richards Allison L. , Avutu Viswatej , Chan Jason E. , Chi Ping , Dickson Mark A. , Gounder Mrinal M. , Keohan Mary Louise , Movva Sujana , Nacev Benjamin A. , Rosenbaum Evan , Adamson Travis , Singer Samuel , Bartlett Edmund K. , Crago Aimee M. , Yoon Sam S. , Hwang Sinchun , Erinjeri Joseph P. , Antonescu Cristina R. , Tap William D. , D'Angelo Sandra P.
Published: April 2023

Normalized Kynurenine Concentrate Over Time
Supplementary Data 2 from A Phase II Study of Epacadostat and Pembrolizumab in Patients with Advanced Sarcoma
Authors: Kelly Ciara M. , Qin Li-Xuan , Whiting Karissa A. , Richards Allison L. , Avutu Viswatej , Chan Jason E. , Chi Ping , Dickson Mark A. , Gounder Mrinal M. , Keohan Mary Louise , Movva Sujana , Nacev Benjamin A. , Rosenbaum Evan , Adamson Travis , Singer Samuel , Bartlett Edmund K. , Crago Aimee M. , Yoon Sam S. , Hwang Sinchun , Erinjeri Joseph P. , Antonescu Cristina R. , Tap William D. , D'Angelo Sandra P.
Published: April 2023

Normalized Tryptophan Concentrate Over Time
Supplemental Figure 7 from Myosin Light-Chain Kinase Inhibition Potentiates the Antitumor Effects of Avapritinib in PDGFRA D842V-Mutant Gastrointestinal Stromal Tumor
Authors: Rossi Ferdinand , Liu Mengyuan , Tieniber Andrew , Etherington Mark S. , Hanna Andrew , Vitiello Gerardo A. , Param Nesteene J. , Do Kevin , Wang Laura , Antonescu Cristina R. , Zeng Shan , Zhang Jennifer Q. , DeMatteo Ronald P.
Published: April 2023

Supplemental Figure 7.
Supplemental Figure 1 from Myosin Light-Chain Kinase Inhibition Potentiates the Antitumor Effects of Avapritinib in PDGFRA D842V-Mutant Gastrointestinal Stromal Tumor
Authors: Rossi Ferdinand , Liu Mengyuan , Tieniber Andrew , Etherington Mark S. , Hanna Andrew , Vitiello Gerardo A. , Param Nesteene J. , Do Kevin , Wang Laura , Antonescu Cristina R. , Zeng Shan , Zhang Jennifer Q. , DeMatteo Ronald P.
Published: April 2023

Supplemental Figure 1.
TS1-9 from Dynamics of Sequence and Structural Cell-Free DNA Landscapes in Small-Cell Lung Cancer
Authors: Sivapalan Lavanya , Iams Wade T. , Belcaid Zineb , Scott Susan C. , Niknafs Noushin , Balan Archana , White James R. , Kopparapu Prasad , Cann Christopher , Landon Blair V. , Pereira Gavin , Velculescu Victor E. , Hann Christine L. , Lovly Christine M. , Anagnostou Valsamo
Published: April 2023

Supplementary Tables S1-S9
Fig S5 from Dynamics of Sequence and Structural Cell-Free DNA Landscapes in Small-Cell Lung Cancer
Authors: Sivapalan Lavanya , Iams Wade T. , Belcaid Zineb , Scott Susan C. , Niknafs Noushin , Balan Archana , White James R. , Kopparapu Prasad , Cann Christopher , Landon Blair V. , Pereira Gavin , Velculescu Victor E. , Hann Christine L. , Lovly Christine M. , Anagnostou Valsamo
Published: April 2023

(A) Overall, 27 patients had cell-free tumor load (cfTL) detected using tumor-derived sequence alterations, of which 20 patients also had evaluable plasma aneuploidy (PA)-based responses. Comparison between ctDNA responses determined using mutation-based and plasma aneuploidy-based responses in these 20 patients revealed significant concordance (p < 0.001, Fisher’s exact test). (B) Concordance was also observed between complete elimination of cfTL based on tumor-derived sequence alterations and plasma aneuploidy dynamics in these patients (p < 0.001, Fisher’s exact test). For these comparisons, plasma aneuploidy dynamics were assessed using a binarized classification of PA scores (PA score > 4.90 indicative of tumor aneuploidy, PA score <4.90 indicative of normal ploidy): PA undetectable (normal ploidy across all timepoints analyzed), PA response (aneuploidy detected at baseline or T1 sampling followed by a reduction to normal ploidy by final sampling), PA response followed by recrudescence (aneuploidy detected at baseline and final sampling with a reduction to normal ploidy at intermediate timepoints), PA progression (aneuploidy detected across all timepoints analyzed). (C) A logistic regression model combining both mutation-based and aneuploidy-based ctDNA responses in these 20 patients demonstrated that the combination of both sequence and structural dynamics outperformed either metric for the prediction of overall radiographic response (Combined model AUC = 0.90, Sequence alterations AUC = 0.85, Structural Alterations AUC = 0.74). (D-E) Further analyses of molecular responses derived from mutation-based analyses of cfTL changes in 27 patients with evaluable tumor-derived mutation trends demonstrated significant associations with both overall (OS) and progression-free (PFS) survival (log-rank p = 0.02 and p < 0.0001, respectively), independent of treatment modality (Chemotherapy vs immunotherapy-containing regimens). (F-G) cfTL elimination according to mutation-based analyses was also predictive of both OS and PFS (log-rank p = 0.01 and P < 0.0001, respectively). (H-I) Similarly, PA-based ctDNA responses showed significant associations with both OS (p =0.003) and PFS (log-rank p=0.001).
Fig S4 from Dynamics of Sequence and Structural Cell-Free DNA Landscapes in Small-Cell Lung Cancer
Authors: Sivapalan Lavanya , Iams Wade T. , Belcaid Zineb , Scott Susan C. , Niknafs Noushin , Balan Archana , White James R. , Kopparapu Prasad , Cann Christopher , Landon Blair V. , Pereira Gavin , Velculescu Victor E. , Hann Christine L. , Lovly Christine M. , Anagnostou Valsamo
Published: April 2023

(A) Genome-wide log2 copy ratios derived from targeted error-correction sequencing (TEC-Seq) data using CNVkit (Methods) are shown for each plasma sample, with copy number gains indicated in red and losses indicated in blue. Each row corresponds to a single plasma sample and rows are ordered with respect to consecutive sampling timepoints analyzed for each patient. (B-F) Genome-wide copy number profiles are shown for patients with matched tumor (WES) and plasma samples analyzed. We observed a high concordance between copy number profiles derived by whole exome sequencing, our approach (CNVkit) and ichorCNA for patients with detectable aneuploidy in plasma. (B) Patient 3 had undetectable ctDNA according to tumor-specific sequence alterations. However, this patient was classified as a molecular responder based on decrease of plasma aneuploidy to normal ploidy by the week 8 timepoint. (C) Patient 5 was classified as a molecular progressor based on the presence of tumor-specific sequence alterations and plasma aneuploidy across all timepoints analyzed. (D) Similarly, patient 9 was classified as a molecular progressor based on the persistence of mutations and plasma aneuploidy, which were detectable across all sampled timepoints from this patient. (E, F) Plasma copy number profiles for patients 11 and 14 indicated ploidy close to normal ploidy across all timepoints analyzed. These patients were classified as molecular responders based on tumor-derived sequence alterations.
Fig S3 from Dynamics of Sequence and Structural Cell-Free DNA Landscapes in Small-Cell Lung Cancer
Authors: Sivapalan Lavanya , Iams Wade T. , Belcaid Zineb , Scott Susan C. , Niknafs Noushin , Balan Archana , White James R. , Kopparapu Prasad , Cann Christopher , Landon Blair V. , Pereira Gavin , Velculescu Victor E. , Hann Christine L. , Lovly Christine M. , Anagnostou Valsamo
Published: April 2023

Sequence alterations that were classified as germline (median 44.9%, range 27.3% - 73.1%) had the highest overall MAFs, compared to both tumor-derived (median 10.2%, range 0.1% - 75.7%) and clonal-hematopoiesis-derived (CH-derived) variants (median 0.8%, range 0.1 – 86.7%). Tumor-derived variants had significantly higher MAFs compared to CH-derived variants. P values were calculated using the Mann-Whitney U test. **** p < 0.0001
Fig S1 from Dynamics of Sequence and Structural Cell-Free DNA Landscapes in Small-Cell Lung Cancer
Authors: Sivapalan Lavanya , Iams Wade T. , Belcaid Zineb , Scott Susan C. , Niknafs Noushin , Balan Archana , White James R. , Kopparapu Prasad , Cann Christopher , Landon Blair V. , Pereira Gavin , Velculescu Victor E. , Hann Christine L. , Lovly Christine M. , Anagnostou Valsamo
Published: April 2023

Schematic summarizing the branched logic used to determine the origin of sequence alterations identified in plasma NGS. Variants representing lung cancer hotspots were classified as tumor-derived, independent of their presence in matched WBC DNA NGS. Variants with a variant allele fraction (VAF) >25% in all WBC DNA and plasma samples from a patient were classified as germline. Alterations that were detected in matched WBC DNA sequencing or in the canonical clonal hematopoiesis (CH) gene DNMT3A were classified as CH-derived. For all variants detected in plasma using TEC-Seq but not in matched WBC DNA samples (based on a threshold of >3 supermutants), we performed an additional evaluation of their supermutant counts in the WBC DNA sequence data to exclude potential CH origin. Plasma variants with a supermutant count of >1 in matched WBC DNA TEC-Seq data were classified as CH-derived and alterations with a matched WBC DNA supermutant count of 0 were assigned a tumor-derived origin.
Supplementary Figure S2 from Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in a Xenograft Model
Authors: Chen Shih-Shih , Barrientos Jacqueline C. , Ferrer Gerardo , King-Richards Morgan , Chen Yu-Ju , Ravichandran Priyadarshini , Ibrahim Michael , Kieso Yasmine , Waters Sheila , Kutok Jeffery L. , Peluso Marisa , Sharma Sujata , Weaver David T. , Pachter Jonathan A. , Rai Kanti R. , Chiorazzi Nicholas
Published: April 2023

Effects of PI3K-gi, PI3K-di on the proliferation and migration of CLL-derived T cells.
Supplementary Figure S1 from Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in a Xenograft Model
Authors: Chen Shih-Shih , Barrientos Jacqueline C. , Ferrer Gerardo , King-Richards Morgan , Chen Yu-Ju , Ravichandran Priyadarshini , Ibrahim Michael , Kieso Yasmine , Waters Sheila , Kutok Jeffery L. , Peluso Marisa , Sharma Sujata , Weaver David T. , Pachter Jonathan A. , Rai Kanti R. , Chiorazzi Nicholas
Published: April 2023

Effects of inhibition of PI3K isoforms on CLL-cell proliferation, survival, and migration.
Data from Multi-center phase I trial of Ivosidenib as Maintenance Treatment following Allogeneic Hematopoietic Cell Transplantation for IDH1-Mutated Acute Myeloid Leukemia
Authors: Fathi Amir T. , Kim Haesook T. , Soiffer Robert J. , Levis Mark J. , Li Shuli , Kim Annette S. , DeFilipp Zachariah , El-Jawahri Areej , McAfee Steve L. , Brunner Andrew M. , Amrein Philip C. , Mims Alice S. , Knight Laura W. , Kelley Devon , Bottoms AJ S. , Perry Lindsey H. , Wahl Jonathan L. , Brock Jennifer , Breton Elayne , Marchione Dylan M. , Ho Vincent T. , Chen Yi-Bin
Published: April 2023

Abstract
Purpose: IDH1 (isocitrate dehydrogenase 1) mutations occur in 5-10% of patients with acute myeloid leukemia (AML). Ivosidenib is an IDH1 inhibitor, approved for use in patients with IDH1-mutated AML. Patients and Methods: We conducted a multi-center, phase I trial of maintenance ivosidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH1-mutated AML. Ivosidenib was initiated between days 30 and 90 following HCT and continued for up to twelve 28-day cycles. The first dose level was 500mg daily, with level reduction to 250mg daily, if needed, in a 3x3 de-escalation design. Ten additional patients would then receive the maximum tolerated (MTD) or recommended phase 2 dose (RP2D). The primary endpoint was establishing the MTD or RP2D of ivosidenib. Results: Eighteen patients were enrolled, of whom 16 initiated post-HCT ivosidenib. One dose limiting toxicity, grade(g) 3 QTc prolongation, was observed. The RP2D was established at 500mg daily. Attributable g≥3 adverse events were uncommon, with the most common being QTc prolongation in 2 patients. Eight patients discontinued maintenance, with only one due to adverse event. Six-month cumulative incidence (CI) of gII-IV aGVHD was 6.3%, and two-year CI of all cGVHD was 63%. Two-year CI of relapse and non-relapse mortality (NRM) were 19% and 0%, respectively. Two-year progression-free (PFS) was 81%, and two-year overall survival (OS) was 88%. Conclusions: Ivosidenib is safe and well-tolerated as maintenance therapy following HCT. Cumulative incidence of relapse and NRM, as well as estimations of PFS and OS, were promising in this phase 1 study.
Data from Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer
Authors: Tolmeijer Sofie H. , Boerrigter Emmy , Sumiyoshi Takayuki , Kwan Edmond M. , Ng Sarah W.S. , Annala Matti , Donnellan Gráinne , Herberts Cameron , Benoist Guillemette E. , Hamberg Paul , Somford Diederik M. , van Oort Inge M. , Schalken Jack A. , Mehra Niven , van Erp Nielka P. , Wyatt Alexander W.
Published: April 2023

AbstractPurpose:
Androgen receptor pathway inhibitors (ARPI) are standard of care for treatment-naïve metastatic castration-resistant prostate cancer (mCRPC), but rapid resistance is common. Early identification of resistance will improve management strategies. We investigated whether changes in circulating tumor DNA (ctDNA) fraction during ARPI treatment are linked with mCRPC clinical outcomes.
Experimental Design:
Plasma cell-free DNA was collected from 81 patients with mCRPC at baseline and after 4 weeks of first-line ARPI treatment during two prospective multicenter observational studies (NCT02426333; NCT02471469). ctDNA fraction was calculated from somatic mutations in targeted sequencing and genome copy-number profiles. Samples were classified into detected versus undetected ctDNA. Outcome measurements were progression-free survival (PFS) and overall survival (OS). Nondurable treatment response was defined as PFS ≤6 months.
Results:
ctDNA was detected in 48/81 (59%) baseline and 29/81 (36%) 4-week samples. ctDNA fraction for samples with detected ctDNA was lower at 4 weeks versus baseline (median 5.0% versus 14.5%, P = 0.017). PFS and OS were shortest for patients with persistent ctDNA at 4 weeks (univariate HR, 4.79; 95% CI, 2.62–8.77 and univariate HR, 5.49; 95% CI, 2.76–10.91, respectively), independent of clinical prognostic factors. For patients exhibiting change from detected to undetected ctDNA by 4 weeks, there was no significant PFS difference versus patients with baseline undetected ctDNA. ctDNA change had a positive predictive value of 88% and negative predictive value of 92% for identifying nondurable responses.
Conclusions:
Early changes in ctDNA fraction are strongly linked to duration of first-line ARPI treatment benefit and survival in mCRPC and may inform early therapy switches or treatment intensification.
Data from Myosin light chain kinase inhibition potentiates the anti-tumor effects of avapritinib in PDGFRA D842V-mutant gastrointestinal stromal tumor
Authors: Rossi Ferdinand , Liu Mengyuan , Tieniber Andrew , Etherington Mark S. , Hanna Andrew , Vitiello Gerardo A. , Param Nesteene J. , Do Kevin , Wang Laura , Antonescu Cristina R. , Zeng Shan , Zhang Jennifer Q. , DeMatteo Ronald P.
Published: April 2023

Abstract
Purpose: To create an in vivo model of PDGFRA D842V-mutant gastrointestinal stromal tumor (GIST) and identify the mechanism of tumor persistence following avapritinib therapy. Experimental Design: We created a patient-derived xenograft of PDGFRA D842V-mutant GIST and tested the effects of imatinib, avapritinib, and ML-7, an inhibitor of myosin light chain kinase (MYLK). Bulk tumor RNA sequencing and oncogenic signaling were evaluated. Apoptosis, survival, and actin cytoskeleton were evaluated in GIST T1 cells and isolated PDX cells in vitro. Human GIST specimens were analyzed for MYLK expression. Results: The PDX was minimally responsive to imatinib but sensitive to avapritinib. Avapritinib therapy increased tumor expression of genes related to the actin cytoskeleton, including MYLK. ML-7 induced apoptosis and disrupted actin filaments in short-term cultures of PDX cells, and decreased survival in GIST T1 cells in combination with imatinib or avapritinib. Combined therapy with ML-7 improved the anti-tumor effects of low dose avapritinib in vivo. Furthermore, MYLK was expressed in human GIST specimens. Conclusions: MYLK upregulation is a novel mechanism of tumor persistence after tyrosine kinase inhibition. Concomitant MYLK inhibition may enable the use of a lower dose of avapritinib, which is associated with dose-dependent cognitive side effects.
Supplementary Figure 8 from BZW2 Inhibition Reduces Colorectal Cancer Growth and Metastasis
Authors: Agarwal Sumit , Afaq Farrukh , Bajpai Prachi , Behring Michael , Kim Hyung-Gyoon , Varambally Amith , Chandrashekar Darshan S. , Peter Shajan , Diffalha Sameer Al , Khushman Moh'd , Seeber Andreas , Varambally Sooryanarayana , Manne Upender
Published: April 2023

S8. EZH2 and BZW2 correlation in CRC cells.
Supplementary Figure 5 from BZW2 Inhibition Reduces Colorectal Cancer Growth and Metastasis
Authors: Agarwal Sumit , Afaq Farrukh , Bajpai Prachi , Behring Michael , Kim Hyung-Gyoon , Varambally Amith , Chandrashekar Darshan S. , Peter Shajan , Diffalha Sameer Al , Khushman Moh'd , Seeber Andreas , Varambally Sooryanarayana , Manne Upender
Published: April 2023

S5. MALAT1 and NEAT1 are downstream target genes of BZW2 in CRC.
Supplementary Figure 1 from BZW2 Inhibition Reduces Colorectal Cancer Growth and Metastasis
Authors: Agarwal Sumit , Afaq Farrukh , Bajpai Prachi , Behring Michael , Kim Hyung-Gyoon , Varambally Amith , Chandrashekar Darshan S. , Peter Shajan , Diffalha Sameer Al , Khushman Moh'd , Seeber Andreas , Varambally Sooryanarayana , Manne Upender
Published: April 2023

S1. BZW2 mRNA overexpression in CRC.
Genetic Associations with Smoking Relapse and Proportion of Follow-up in Smoking Relapse throughout Adulthood in Pre- and Postmenopausal Women
Authors: Jones Stephanie K. , Alberg Anthony J. , Wallace Kristin , Froeliger Brett , Carpenter Matthew J. , Wolf Bethany
Published: April 2023

Genetics contribute to smoking cessation, which is important for cancer prevention. Prior genetic studies, limited by short-term follow-up, have not examined multiple quit attempts and relapse events experienced by most smokers. This research investigated genetic associations with smoking relapse throughout adulthood. Participants were from two, all-female longitudinal cohort studies and included 12,060 European ancestry ever-smokers with existing genotype data who quit smoking at ≥1 timepoint. Median follow-up was 32 years. Associations between selected SNPs and odds of relapse and, conditional on relapse, SNP associations with proportion of follow-up relapsed were modeled using zero-inflated beta regression. Genotype by menopausal status interactions were evaluated. Women with AA genotypes for CHRNA5 SNP rs16969968 G>A or CHRNA3 SNP rs1051730 G>A (P-value = 0.04 for both) had lower odds of relapse. Among women who relapsed, those with CC genotypes of CHRNA5 SNPs rs588765 T>C (P-value = 0.04) and rs680244 T>C (P-value = 0.048) and AA genotype of DRD2 SNP rs6277 G>A (P-value = 0.01) had higher proportion follow-up in relapse. Associations were stronger among postmenopausal women (genotype by menopause interactions: rs588765 P-value = 0.003, rs680244 P-value = 0.001, rs6277 P-value = 0.04). Women with AA or AG genotypes for COMT SNP rs4680 G>A (P-value = 0.03) had lower proportion follow-up relapsed. This study identified SNP associations with likelihood of relapse or proportion of follow-up in relapse. Several associations were stronger among postmenopausal women. The findings demonstrate the importance of long-term follow-up and factors unique to women when characterizing smoking phenotypes.

Prevention Relevance:

This study is the first to quantify genetic associations with smoking relapse among female smokers throughout adulthood. These findings could inform precision medicine approaches to improve long-term smoking relapse prevention to reduce smoking attributable cancer morbidity and mortality.
T Cells Expressing a Modified FcγRI Exert Antibody-Dependent Cytotoxicity and Overcome the Limitations of CAR T-cell Therapy against Solid Tumors
Authors: Rasoulouniriana Diana , Santana-Magal Nadine , Gutwillig Amit , Farhat-Younis Leen , Tal Lior , Amar Sarah , Milyavsky Michael , Muddineni Siva Sai Naga Anurag , Solomon Neta , Shpilt Hana , Dotan Shahar , Pilpel Noam , Waskow Claudia , Feinmesser Meora , Rider Peleg , Carmi Yaron
Published: April 2023

The pioneering design of chimeric antigen receptor (CAR) T-cell therapy demonstrated the potential of reprogramming the immune system. Nonetheless, T-cell exhaustion, toxicity, and suppressive microenvironments limit their efficacy in solid tumors. We previously characterized a subset of tumor-infiltrating CD4+ T cells expressing the FcγRI receptor. Herein, we detail engineering of a receptor, based on the FcγRI structure, allowing T cells to target tumor cells using antibody intermediates. These T cells showed effective and specific cytotoxicity only when an appropriate antibody was added. Only target-bound antibodies activated these cells, while free antibodies were internalized without activation. Their cytotoxic activity was correlated to target protein density, therefore targeting tumor cells with high antigen density while sparing normal cells with low or no expression. This activation mechanism prevented premature exhaustion. Furthermore, during antibody-dependent cytotoxicity these cells secreted attenuated cytokine levels compared with CAR T cells, thereby enhancing their safety profile. These cells eradicated established melanomas, infiltrated the tumor microenvironment, and facilitated host immune cell recruitment in immunocompetent mice. In NOD/SCID gamma mice the cells infiltrate, persist, and eradicate tumors. As opposed to CAR T-cell therapies, which require changing the receptor across different types of cancer, our engineered T cells remain the same across tumor types, while only the injected antibody changes. Overall, we generated a highly flexible T-cell therapy capable of binding a wide range of tumor cells with high affinity, while preserving the cytotoxic specificity only to cells expressing high density of tumor-associated antigens and using a single manufacturing process.
Table S2 from Identification of Membrane-expressed CAPRIN-1 as a Novel and Universal Cancer Target, and Generation of a Therapeutic Anti-CAPRIN-1 Antibody TRK-950
Authors: Okano Fumiyoshi , Saito Takanori , Minamida Yoshitaka , Kobayashi Shinichi , Ido Takayoshi , Miyauchi Yasushi , Wasai Ukei , Akazawa Daisuke , Kume Masahiko , Ishibashi Masaki , Jiang Ke , Aicher Alexandra , Heeschen Christopher , Yonehara Tetsu
Published: April 2023

Toxicokinetics of TRK-950 in Cynomolgus Monkeys
Figure S6 from Identification of Membrane-expressed CAPRIN-1 as a Novel and Universal Cancer Target, and Generation of a Therapeutic Anti-CAPRIN-1 Antibody TRK-950
Authors: Okano Fumiyoshi , Saito Takanori , Minamida Yoshitaka , Kobayashi Shinichi , Ido Takayoshi , Miyauchi Yasushi , Wasai Ukei , Akazawa Daisuke , Kume Masahiko , Ishibashi Masaki , Jiang Ke , Aicher Alexandra , Heeschen Christopher , Yonehara Tetsu
Published: April 2023

CAPRIN-1 expression on the cell membrane increases due to stressful stimuli to the cancer cells.
Figure S2 from Identification of Membrane-expressed CAPRIN-1 as a Novel and Universal Cancer Target, and Generation of a Therapeutic Anti-CAPRIN-1 Antibody TRK-950
Authors: Okano Fumiyoshi , Saito Takanori , Minamida Yoshitaka , Kobayashi Shinichi , Ido Takayoshi , Miyauchi Yasushi , Wasai Ukei , Akazawa Daisuke , Kume Masahiko , Ishibashi Masaki , Jiang Ke , Aicher Alexandra , Heeschen Christopher , Yonehara Tetsu
Published: April 2023

CAPRIN-1 correlated to the cell proliferation and viability.
Supplementary File 9 from Integrative metatranscriptomic analysis reveals disease-specific microbiome-host interactions in oral squamous cell carcinoma
Authors: Jain Vinay , Baraniya Divyashri , Elhadedy Doaa E , Chen Tsute , Slifker Michael J. , Alakwaa Fadhl , Cai Kathy Q. , Chitrala Kumaraswamy Naidu , Fundakowski Christopher , Al-hebshi Nezar
Published: April 2023

Differentially abundant microbial enzyme classes (EC) and metabolic pathways (MaAsLin2).
Supplementary File 8 from Integrative metatranscriptomic analysis reveals disease-specific microbiome-host interactions in oral squamous cell carcinoma
Authors: Jain Vinay , Baraniya Divyashri , Elhadedy Doaa E , Chen Tsute , Slifker Michael J. , Alakwaa Fadhl , Cai Kathy Q. , Chitrala Kumaraswamy Naidu , Fundakowski Christopher , Al-hebshi Nezar
Published: April 2023

Differentially abundant microbial taxa (MaAsLin2)
Supplementary File 6 from Integrative metatranscriptomic analysis reveals disease-specific microbiome-host interactions in oral squamous cell carcinoma
Authors: Jain Vinay , Baraniya Divyashri , Elhadedy Doaa E , Chen Tsute , Slifker Michael J. , Alakwaa Fadhl , Cai Kathy Q. , Chitrala Kumaraswamy Naidu , Fundakowski Christopher , Al-hebshi Nezar
Published: April 2023

Microbial relative transcriptional abundances in the samples.
Supplementary File 5 from Integrative metatranscriptomic analysis reveals disease-specific microbiome-host interactions in oral squamous cell carcinoma
Authors: Jain Vinay , Baraniya Divyashri , Elhadedy Doaa E , Chen Tsute , Slifker Michael J. , Alakwaa Fadhl , Cai Kathy Q. , Chitrala Kumaraswamy Naidu , Fundakowski Christopher , Al-hebshi Nezar
Published: April 2023

Host differentially expressed genes and pathways by lymph node status
Supplementary File 12 from Integrative metatranscriptomic analysis reveals disease-specific microbiome-host interactions in oral squamous cell carcinoma
Authors: Jain Vinay , Baraniya Divyashri , Elhadedy Doaa E , Chen Tsute , Slifker Michael J. , Alakwaa Fadhl , Cai Kathy Q. , Chitrala Kumaraswamy Naidu , Fundakowski Christopher , Al-hebshi Nezar
Published: April 2023

Host pathways (GSEA genesets) correlating with microbial enzyme classes