bluuebunny/crossref_metadata_2025 huggingface dataset:
Design and Analysis of Stochastic Processing and Matching Networks
Authors: Jhunjhunwala Prakirt Raj
Published: January 2024

Stochastic Processing Networks (SPNs) [24] are ubiquitous in engineering with applications in Data Centers (eg. packet routing), Telecommunication (eg. call centers), Transportation, etc. Stochastic Matching Networks (SMNs) are newly emerging variation of SPNs where 'jobs' and 'servers' arrive in the system and are matched using a decision rule. SMNs have applications in Online matching markets (eg. uber platform), Healthcare (eg. kidney transplant), Quantum Networks, Assemble-to-order (eg. manufacturing plants) and many other crucial problems. The aim of my research is to design provably efficient decision-making policies for Stochastic Processing Networks (SPNs) and Stochastic Matching Networks (SMNs) and develop analytical tools to obtain performance guarantees on their throughput and delay.
Impact of ovary-intact menopause in a mouse model of heart failure with preserved ejection fraction
Authors: Troy Aaron M. , Normukhamedova Diyora , Grothe Daniela , Momen Abdul , Zhou Yu-Qing , McFadden Meghan , Hussain Mansoor , Billia Filio , Cheng Hai-Ling Margaret
Published: January 2024

This is the first preclinical study to examine the impact of ovary-intact menopause [accelerated ovarian failure (AOF)] on HFpEF. Echocardiography of young female mice revealed early evidence of diastolic and systolic cardiac dysfunction apparent only on strain imaging in HFpEF only, AOF only, or the combination. Surprisingly, AOF did not exacerbate the HFpEF phenotype. Results in middle-aged “old” females also showed no interaction between HFpEF and AOF and, importantly, no cardiovascular impact from HFpEF or AOF.
Multitargets Orientation Technique Based on Reflection Characteristic Analysis Using an Inverse Diffraction Parabolic Equation
Authors: Guo Qi , Sun Daozong , Li Zhen , Lyu Shilei , Xue Xiuyun
Published: January 2024

In this article, the inverse diffraction parabolic equation (IDPE) model based on the finite difference method is proposed, which is first applied in the multiple nonradiation targets orientation technology. In principle, the electromagnetic signal propagating in the transmission path will produce a reflected signal back to the source end while encountering the discontinuous objects. The distribution of the reflection or refraction intensity is directly associated with the distances and heights of the objects, so the location can be determined by means of analyzing the distribution. Here, according to the profile data of field intensity at the source end, the distribution of backward propagating electromagnetic waves are calculated rapidly by the IDPE. Then, the local extreme searching method is applied to search the coordinate of the convergence point of field intensity and the positions of multiple objects are finally determined. The piecewise linear function is used to model the irregular terrain. The influence of discontinuous terrain slopes on the false alarm probability of objects localization is also analyzed. The results show that the localization accuracy of the IDPE algorithm is affected by multiple factors, such as the radio frequency and sampling interval of field intensity. It is proved that the IDPE is a novel and efficient algorithm for multiple nonradiation targets orientation technology in long-range complicated terrain environment.
Usefulness of Once‐Weekly GLP‐1 Receptor Agonist Semaglutide on Glycemic Control in Subjects with Type 2 Diabetes Mellitus: Switching from the Same Class Dulaglutide in a Retrospective Observation Study
Authors: Kimura Tomohiko , Kubo Masato , Takahashi Kaio , Wamata Ryo , Iwamoto Yuichiro , Iwamoto Hideyuki , Katakura Yukino , Sanada Junpei , Fushimi Yoshiro , Shimoda Masashi , Tatsumi Fuminori , Nakanishi Shuhei , Mune Tomoatsu , Kaku Kohei , Kaneto Hideaki
Published: January 2024

Recently, the development of once‐weekly incretin‐based injections dulaglutide and semaglutide has drawn a great deal of attention. This study is aimed at comparing the efficacy of once‐weekly GLP‐1 receptor activator (GLP‐1RA) dulaglutide and semaglutide on glycemic control and several metabolic parameters in patients with type 2 diabetes mellitus. We compared various clinical parameters between before and after switching from dulaglutide to semaglutide in “study 1” (pre‐post comparison) and set the control group using propensity score matching method in “study 2.” In “study 1,” six months after the switching, HbA1c was significantly reduced from 8.2% to 7.6% and body mass index was also decreased from 30.4 kg/m2 to 30.0 kg/m2. Such effects were more pronounced in subjects whose glycemic control was poor. In “study 2,” after 1 : 1 propensity score matching, glycemic control and body weight management were improved in the switching group compared with the dulaglutide continuation group. In this study including obese subjects with poor glycemic control, switching dulaglutide to semaglutide showed more beneficial effects on both glycemic and weight control irrespective of age, body weight, and diabetes duration. Therefore, we should bear in mind that it would be better to start using a relatively new once‐weekly GLP‐1RA semaglutide in clinical practice, especially in obese subjects with poor glycemic control with other GLP‐1RAs.
Federated Medical Learning Framework Based on Blockchain and Homomorphic Encryption
Authors: Yang Xiaohui , Xing Chongbo
Published: January 2024

Federated learning-based medical data privacy sharing can promote the development of medical industry intelligence, but limited by its own security and privacy deficiencies, federated learning still suffers from a single point of failure and privacy leakage of intermediate parameters. To address these problems, this paper proposes a privacy protection framework for medical data based on blockchain and cross-silo federated learning, using cross-silo federated learning to establish a collaborative training platform for multiple medical institutions to enhance the privacy of medical data, introducing blockchain and smart contracts to realize decentralized federated learning to enhance trust between distrustful medical institutions and solve the problem of a single point of failure. In addition, a secure aggregation scheme is designed using threshold homomorphic encryption to prevent the privacy leakage problem during parameter transmission. The experimental and analytical results show that the accuracy of this paper’s scheme is consistent with the original federated learning scheme, effectively deals with the problems of single-point failure and inference attacks of federated learning, improves system robustness, and is suitable for medical scenarios with more stringent requirements on security and accuracy.
Developing a Content Model of a Mobile-Based Application to Manage Patients with Low-Back and Neck Pain
Authors: Farjami Rad Yasaman , Shahmoradi Leila , Nakhostin Ansari Noureddin , Hasson Scott , Ebrahimi Maryam , Rahmani Katigari Meysam
Published: January 2024

Introduction. As a complementary tool in health, the design of mobile applications to influence care and increase awareness of patients has grown a lot. The purpose of this study is to design and validate the content model of a mobile-based application for managing patients with low-back and neck pain. Methods. This descriptive-analytical study was conducted in two main stages to determine the content model of the application. The first stage consisted of three steps: finding the right exercise, determining the right scale to assess the pain intensity, and determining the appropriate features of the application. In the second stage, data elements collected from the previous stage were prepared in the form of a questionnaire that was given to 12 experts in physical therapy and sports medicine for validation. After collecting the questionnaire, data elements in all parts were analyzed based on the content validity ratio (CVR) and descriptive statistics indicators. Result. The content of the application was prepared in the three axes of exercises for low-back and neck pain, assessment of pain intensity, and features of the application. In the axis of sports exercises, 8 exercises for back pain and 3 exercises for neck pain were included according to the reference books. A Functional Rating Index (FRI) scale with 10 elements was selected in the axis of determining pain intensity. Also, 12 features such as the daily exercise section, using the animation, and using an audio file to explain how to do exercises were included in the model. Conclusion. According to the gaps identified in the existing applications, determining the content model of the application that is based on evidence and according to the opinion of experts is useful in improving the apps. The content model of this study was presented in 3 axes to increase the patient’s willingness to do exercises, the correct way to perform exercises, conservative treatment, and check the progress of the treatment. The software developers can use these findings as a basis for designing new apps to manage low-back pain and neck pain.
Joint Optimization of Item and Pod Storage Assignment Problems with Picking Aisles’ Workload Balance in Robotic Mobile Fulfillment Systems
Authors: Zhang Jun , Tian Lingkun , Zhou Zijuan
Published: January 2024

The item and pod storage assignment problems, two critical issues at the strategic level in robotic mobile fulfillment systems, have a strong correlation and should be studied together. Moreover, the workload balance in each picking aisle needs to be considered in the storage assignment problems to avoid robots’ congestion within picking aisles. Motivated by these, the joint optimization of item and pod storage assignment problems (J-IPSAP) with picking aisles’ workload balance is studied. The mixed integer programming model of the J-IPSAP with the workload balance constraint is formulated to minimize the robots’ movement distance. The improved genetic algorithm (IGA) with the decentralized pod storage assignment strategy is designed to solve the J-IPSAP model. The experimental results show that the IGA can obtain high-quality solutions when compared with Gurobi and the two-stage heuristic algorithms. The robots’ movement distance is smallest when the width-to-length ratio of the storage area is close to 1, and the robots’ movement distance will increase with more stringent workload balance constraints.
Hematocrit Is Associated with Cancer-Related Fatigue in Colorectal Cancer Survivors: A Longitudinal Analysis
Authors: Kiebach Joann , de Vries-ten Have Judith , van Duijnhoven Fränzel J.B. , Kok Dieuwertje E. , van Lanen Anne-Sophie , Kouwenhoven Ewout A. , de Wilt Johannes H.W. , Schrauwen Ruud W.M. , Kampman Ellen , Winkels Renate M. , Wesselink Evertine
Published: January 2024

Background:

Cancer-related fatigue (CRF) is a frequent symptom in colorectal cancer survivors. It is unknown to what extent anemia may contribute to CRF in colorectal cancer survivors. This study aimed to investigate the association between hematocrit, as marker for anemia, and CRF among colorectal cancer survivors from diagnosis until two years thereafter.

Methods:

The study population included 1,506 newly diagnosed colorectal cancer survivors at any stage of disease from a prospective cohort study. Hematocrit and CRF (EORTC QLQ-C30) were assessed at diagnosis, six months, and two years after diagnosis. Multivariable logistic regression or multivariable linear mixed models were used to assess the associations of hematocrit with CRF prevalence, or CRF severity over time, respectively.

Results:

A low hematocrit (levels <40% men/<36% women) was present in a third of the survivors at diagnosis and six months thereafter, and among 16% two years after diagnosis. The prevalence of CRF was 15% at diagnosis, peaked at 27% at six months, and was 14% two years after diagnosis. Hematocrit was associated with the prevalence of CRF at diagnosis [OR, 0.92; confidence interval (CI), 0.88–0.95], 6 months (OR, 0.89; 95% CI, 0.86–0.92), and 2 years (OR, 0.91; CI, 0.87–0.96) after diagnosis. Lower hematocrit was associated with higher severity of CRF over time (beta-coefficient = 1.3; CI, 1.5–1.1).

Conclusions:

Lower hematocrit levels were longitudinally associated with a higher prevalence and severity of CRF in colorectal cancer.

Impact:

Our findings emphasize the importance of long-term anemia monitoring and a potential role of anemia in CRF among colorectal cancer survivors.
Supplementary Table S3 from PHF6-altered T-ALL Harbor Epigenetic Repressive Switch at Bivalent Promoters and Respond to 5-Azacitidine and Venetoclax
Authors: Pinton Antoine , Courtois Lucien , Doublet Charlotte , Cabannes-Hamy Aurélie , Andrieu Guillaume , Smith Charlotte , Balducci Estelle , Cieslak Agata , Touzart Aurore , Simonin Mathieu , Lhéritier Véronique , Huguet Françoise , Balsat Marie , Dombret Hervé , Rousselot Philippe , Spicuglia Salvatore , Macintyre Elizabeth , Boissel Nicolas , Asnafi Vahid
Published: January 2024

Patient cohort used for in vitro drug sensitivity assay.
Supplementary Data 1 from A Phase II Basket Trial of Dual Anti–CTLA-4 and Anti–PD-1 Blockade in Rare Tumors (DART SWOG 1609 Cohort 47) in Patients with Gestational Trophoblastic Neoplasia
Authors: Patel Sandip P. , Othus Megan , Chae Young Kwang , Dennis Michael J. , Gordon Sarah , Mutch David , Samlowski Wolfram , Robinson William R. “Rusty” , Sharon Elad , Ryan Christopher , Lopez Gabby , Plets Melissa , Blanke Charles , Kurzrock Razelle
Published: January 2024

Supplemental table 1 and supplemental figure 1
Supplementary Table S2 from Intraoperative Integrated Diagnostic System for Malignant Central Nervous System Tumors
Authors: Hayashi Takahiro , Tateishi Kensuke , Matsuyama Shinichiro , Iwashita Hiromichi , Miyake Yohei , Oshima Akito , Honma Hirokuni , Sasame Jo , Takabayashi Katsuhiro , Sugino Kyoka , Hirata Emi , Udaka Naoko , Matsushita Yuko , Kato Ikuma , Hayashi Hiroaki , Nakamura Taishi , Ikegaya Naoki , Takayama Yutaro , Sonoda Masaki , Oka Chihiro , Sato Mitsuru , Isoda Masataka , Kato Miyui , Uchiyama Kaho , Tanaka Tamon , Muramatsu Toshiki , Miyake Shigeta , Suzuki Ryosuke , Takadera Mutsumi , Tatezuki Junya , Ayabe Junichi , Suenaga Jun , Matsunaga Shigeo , Miyahara Kosuke , Manaka Hiroshi , Murata Hidetoshi , Yokoyama Takaakira , Tanaka Yoshihide , Shuto Takashi , Ichimura Koichi , Kato Shingo , Yamanaka Shoji , Cahill Daniel P. , Fujii Satoshi , Shankar Ganesh M. , Yamamoto Tetsuya
Published: January 2024

Mismatch ratio for genomic alterations in the retrospective cohort
Figure S3 from Tumor-Infiltrating CD103+ Tissue-Resident Memory T Cells and CD103−CD8+ T Cells in HNSCC Are Linked to Outcome in Primary but not Metastatic Disease
Authors: von Witzleben Adrian , Ellis Matthew , Thomas Gareth J. , Hoffmann Thomas K. , Jackson Richard , Laban Simon , Ottensmeier Christian H.
Published: January 2024

suppl. Figure 3
Figure S2 from Tumor-Infiltrating CD103+ Tissue-Resident Memory T Cells and CD103−CD8+ T Cells in HNSCC Are Linked to Outcome in Primary but not Metastatic Disease
Authors: von Witzleben Adrian , Ellis Matthew , Thomas Gareth J. , Hoffmann Thomas K. , Jackson Richard , Laban Simon , Ottensmeier Christian H.
Published: January 2024

suppl. Figure 2
Supplementary Table S2 from Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of AGS15E Monotherapy in Patients with Metastatic Urothelial Carcinoma
Authors: Petrylak Daniel P. , Eigl Bernhard J. , George Saby , Heath Elisabeth I. , Hotte Sebastien J. , Chism David D. , Nabell Lisle M. , Picus Joel , Cheng Susanna Y. , Appleman Leonard J. , Sonpavde Guru P. , Morgans Alicia K. , Pourhosseini Pourya , Wu Ruishan , Standley Laura , Croitoru Ruslan , Yu Evan Y.
Published: January 2024

Supplementary Table S2. Representativeness of Study Participants
Figure S2 from Comprehensive DNA Methylation Profiling of Medullary Thyroid Carcinoma: Molecular Classification, Potential Therapeutic Target, and Classifier System
Authors: Shen Cenkai , Shi Xiao , Wen Duo , Zhang Yuqing , Du Yuxin , Zhang Yu , Ma Ben , Tang Haitao , Yin Min , Huang Naisi , Liao Tian , Zhang Ting-Ting , Kong Chang’e , Wei Wenjun , Ji Qinghai , Wang Yu
Published: January 2024

Detailed methylation profile of DMR associated with NNAT
Figure S1 from Comprehensive DNA Methylation Profiling of Medullary Thyroid Carcinoma: Molecular Classification, Potential Therapeutic Target, and Classifier System
Authors: Shen Cenkai , Shi Xiao , Wen Duo , Zhang Yuqing , Du Yuxin , Zhang Yu , Ma Ben , Tang Haitao , Yin Min , Huang Naisi , Liao Tian , Zhang Ting-Ting , Kong Chang’e , Wei Wenjun , Ji Qinghai , Wang Yu
Published: January 2024

Classification and prediction effects of methylation-based MTC clustering system
Supplementary Table S7 from Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naïve Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study
Authors: Drew Yvette , Kim Jae-Weon , Penson Richard T. , O'Malley David M. , Parkinson Christine , Roxburgh Patricia , Plummer Ruth , Im Seock-Ah , Imbimbo Martina , Ferguson Michelle , Rosengarten Ora , Steeghs Neeltje , Kim Min Hwan , Gal-Yam Einav , Tsoref Daliah , Kim Jae-Hoon , You Benoit , De Jonge Maja , Lalisang Roy , Gort Eelke , Bastian Sara , Meyer Kassondra , Feeney Laura , Baker Nigel , Ah-See Mei-Lin , Domchek Susan M. , Banerjee Susana
Published: January 2024

Dose interruptions/delays and reductions
Supplementary Table S4 from Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naïve Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study
Authors: Drew Yvette , Kim Jae-Weon , Penson Richard T. , O'Malley David M. , Parkinson Christine , Roxburgh Patricia , Plummer Ruth , Im Seock-Ah , Imbimbo Martina , Ferguson Michelle , Rosengarten Ora , Steeghs Neeltje , Kim Min Hwan , Gal-Yam Einav , Tsoref Daliah , Kim Jae-Hoon , You Benoit , De Jonge Maja , Lalisang Roy , Gort Eelke , Bastian Sara , Meyer Kassondra , Feeney Laura , Baker Nigel , Ah-See Mei-Lin , Domchek Susan M. , Banerjee Susana
Published: January 2024

Serious AEs
Supplementary Table S3 from Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naïve Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study
Authors: Drew Yvette , Kim Jae-Weon , Penson Richard T. , O'Malley David M. , Parkinson Christine , Roxburgh Patricia , Plummer Ruth , Im Seock-Ah , Imbimbo Martina , Ferguson Michelle , Rosengarten Ora , Steeghs Neeltje , Kim Min Hwan , Gal-Yam Einav , Tsoref Daliah , Kim Jae-Hoon , You Benoit , De Jonge Maja , Lalisang Roy , Gort Eelke , Bastian Sara , Meyer Kassondra , Feeney Laura , Baker Nigel , Ah-See Mei-Lin , Domchek Susan M. , Banerjee Susana
Published: January 2024

AEs by maximum reported grade
Supplementary Table S6 from Proteomic Profiling of Advanced Melanoma Patients to Predict Therapeutic Response to Anti-PD-1 Therapy
Authors: Zila Nina , Eichhoff Ossia M. , Steiner Irene , Mohr Thomas , Bileck Andrea , Cheng Phil F. , Leitner Alexander , Gillet Ludovic , Sajic Tatjana , Goetze Sandra , Friedrich Betty , Bortel Patricia , Strobl Johanna , Reitermaier René , Hogan Sabrina A. , Martínez Gómez Julia M. , Staeger Ramon , Tuchmann Felix , Peters Sophie , Stary Georg , Kuttke Mario , Elbe-Bürger Adelheid , Hoeller Christoph , Kunstfeld Rainer , Weninger Wolfgang , Wollscheid Bernd , Dummer Reinhard , French Lars E. , Gerner Christopher , Aebersold Ruedi , Levesque Mitchell P. , Paulitschke Verena
Published: January 2024

Results of the Wilcoxon rank sum tests, dependent variable = first component of the PCA.
Supplementary Figure S2 from Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naïve Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study
Authors: Drew Yvette , Kim Jae-Weon , Penson Richard T. , O'Malley David M. , Parkinson Christine , Roxburgh Patricia , Plummer Ruth , Im Seock-Ah , Imbimbo Martina , Ferguson Michelle , Rosengarten Ora , Steeghs Neeltje , Kim Min Hwan , Gal-Yam Einav , Tsoref Daliah , Kim Jae-Hoon , You Benoit , De Jonge Maja , Lalisang Roy , Gort Eelke , Bastian Sara , Meyer Kassondra , Feeney Laura , Baker Nigel , Ah-See Mei-Lin , Domchek Susan M. , Banerjee Susana
Published: January 2024

Individual patient percent change from baseline in target tumor size by best objective response in the (A) gBRCAm expansion doublet cohort, (B) non-gBRCAm doublet cohort, and (C) non-gBRCAm triplet cohort
Supplementary Appendix S1 from Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naïve Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study
Authors: Drew Yvette , Kim Jae-Weon , Penson Richard T. , O'Malley David M. , Parkinson Christine , Roxburgh Patricia , Plummer Ruth , Im Seock-Ah , Imbimbo Martina , Ferguson Michelle , Rosengarten Ora , Steeghs Neeltje , Kim Min Hwan , Gal-Yam Einav , Tsoref Daliah , Kim Jae-Hoon , You Benoit , De Jonge Maja , Lalisang Roy , Gort Eelke , Bastian Sara , Meyer Kassondra , Feeney Laura , Baker Nigel , Ah-See Mei-Lin , Domchek Susan M. , Banerjee Susana
Published: January 2024

MEDIOLA Investigators, Supplementary Methods, and Supplementary Results
Supplementary Fig. S1 from Proteomic Profiling of Advanced Melanoma Patients to Predict Therapeutic Response to Anti-PD-1 Therapy
Authors: Zila Nina , Eichhoff Ossia M. , Steiner Irene , Mohr Thomas , Bileck Andrea , Cheng Phil F. , Leitner Alexander , Gillet Ludovic , Sajic Tatjana , Goetze Sandra , Friedrich Betty , Bortel Patricia , Strobl Johanna , Reitermaier René , Hogan Sabrina A. , Martínez Gómez Julia M. , Staeger Ramon , Tuchmann Felix , Peters Sophie , Stary Georg , Kuttke Mario , Elbe-Bürger Adelheid , Hoeller Christoph , Kunstfeld Rainer , Weninger Wolfgang , Wollscheid Bernd , Dummer Reinhard , French Lars E. , Gerner Christopher , Aebersold Ruedi , Levesque Mitchell P. , Paulitschke Verena
Published: January 2024

Differentially expressed proteins (DEPs) and functional annotation of NR proteomes based on GO term classification.
Supplementary Figure S2 from PHF6-altered T-ALL Harbor Epigenetic Repressive Switch at Bivalent Promoters and Respond to 5-Azacitidine and Venetoclax
Authors: Pinton Antoine , Courtois Lucien , Doublet Charlotte , Cabannes-Hamy Aurélie , Andrieu Guillaume , Smith Charlotte , Balducci Estelle , Cieslak Agata , Touzart Aurore , Simonin Mathieu , Lhéritier Véronique , Huguet Françoise , Balsat Marie , Dombret Hervé , Rousselot Philippe , Spicuglia Salvatore , Macintyre Elizabeth , Boissel Nicolas , Asnafi Vahid
Published: January 2024

Supplementary Figure 2 (A) Bar graphs showing the significant association between PHF6 status and methylation clusters previously described by our team (1). (B) Kaplan-Meier curve of overall survival between PHF6ALT and PHF6WT patients within the cluster 5 (Top).
Table depicting the number of individuals according to timepoints.
Table S5 from Risk Factors Associated with Durable Progression-Free Survival in Patients with Relapsed or Refractory Multiple Myeloma Treated with Anti-BCMA CAR T-cell Therapy
Authors: Zhang Mingming , Zhou Linghui , Zhao Houli , Zhang Yanlei , Wei Guoqing , Hong Ruimin , Wu Wenjun , Xu Huijun , Wang Linqin , Ni Fang , Cui Jiazhen , Peng Shuixiu , Huang Chih-Hua , Chang Alex H. , Hu Yongxian , Huang He
Published: January 2024

Supplementary table S5 Univariate analysis for CIR for MM patients with ant-BCMA CAR-T therapy
Figure S6 from Risk Factors Associated with Durable Progression-Free Survival in Patients with Relapsed or Refractory Multiple Myeloma Treated with Anti-BCMA CAR T-cell Therapy
Authors: Zhang Mingming , Zhou Linghui , Zhao Houli , Zhang Yanlei , Wei Guoqing , Hong Ruimin , Wu Wenjun , Xu Huijun , Wang Linqin , Ni Fang , Cui Jiazhen , Peng Shuixiu , Huang Chih-Hua , Chang Alex H. , Hu Yongxian , Huang He
Published: January 2024

Supplementary figure S6 Overall survival (OS) and subgroup analysis among 61 patients. A: The OS in all patients; B: The OS in patients with light chain or other types. C: The OS in patients among different ECOG scores. D: The OS in patients with different number of independent factors.
Figure S5 from Risk Factors Associated with Durable Progression-Free Survival in Patients with Relapsed or Refractory Multiple Myeloma Treated with Anti-BCMA CAR T-cell Therapy
Authors: Zhang Mingming , Zhou Linghui , Zhao Houli , Zhang Yanlei , Wei Guoqing , Hong Ruimin , Wu Wenjun , Xu Huijun , Wang Linqin , Ni Fang , Cui Jiazhen , Peng Shuixiu , Huang Chih-Hua , Chang Alex H. , Hu Yongxian , Huang He
Published: January 2024

Supplementary figure S5 Representative imaging observations before and after CAR-T therapy
Figure S4 from Risk Factors Associated with Durable Progression-Free Survival in Patients with Relapsed or Refractory Multiple Myeloma Treated with Anti-BCMA CAR T-cell Therapy
Authors: Zhang Mingming , Zhou Linghui , Zhao Houli , Zhang Yanlei , Wei Guoqing , Hong Ruimin , Wu Wenjun , Xu Huijun , Wang Linqin , Ni Fang , Cui Jiazhen , Peng Shuixiu , Huang Chih-Hua , Chang Alex H. , Hu Yongxian , Huang He
Published: January 2024

Supplementary figure S4 CRS grade distribution in 61 patients
Figure S2 from Risk Factors Associated with Durable Progression-Free Survival in Patients with Relapsed or Refractory Multiple Myeloma Treated with Anti-BCMA CAR T-cell Therapy
Authors: Zhang Mingming , Zhou Linghui , Zhao Houli , Zhang Yanlei , Wei Guoqing , Hong Ruimin , Wu Wenjun , Xu Huijun , Wang Linqin , Ni Fang , Cui Jiazhen , Peng Shuixiu , Huang Chih-Hua , Chang Alex H. , Hu Yongxian , Huang He
Published: January 2024

Supplementary figure S2 (A) CAR expression in T cells after lentiviral transduction was analyzed by flow cytometry analysis. From left to right, non-transduced T cells as a control, T cells transduced with YK-BCMA BB-002 CAR vector. CAR expression was monitored by biotinylated goat anti-mouse and anti-human antibodies (Jackson ImmunoResearch Laboratories, Inc.), followed by APC-labelled streptavidin (BD Pharmingen). (B) Cytotoxicity as using BCMA-directed CAR T-cells co-cultured with HeLa-BCMA cells at various E.T. ratios (0.25:1, 0.5:1, 1:1, and 5:1, respectively). Compared with control T cells, BCMA-directed CAR T-cells demonstrated very strong cytotoxicity towards target cells, even at very low E:T ratios.
Data from Inhibition of PORCN Blocks Wnt Signaling to Attenuate Progression of Oral Carcinogenesis
Authors: Peña-Oyarzún Daniel , Flores Tania , Torres Vicente A. , Quest Andrew F.G. , Lobos-González Lorena , Kretschmar Catalina , Contreras Pamela , Maturana-Ramírez Andrea , Criollo Alfredo , Reyes Montserrat
Published: January 2024

AbstractPurpose:
Oral squamous cell carcinoma (OSCC) is commonly preceded by potentially malignant lesions, referred to as oral dysplasia. We recently reported that oral dysplasia is associated with aberrant activation of the Wnt/β-catenin pathway, due to overexpression of Wnt ligands in a Porcupine (PORCN)-dependent manner. Pharmacologic inhibition of PORCN precludes Wnt secretion and has been proposed as a potential therapeutic approach to treat established cancers. Nevertheless, there are no studies that explore the effects of PORCN inhibition at the different stages of oral carcinogenesis.
Experimental Design:
We performed a model of tobacco-induced oral cancer in vitro, where dysplastic oral keratinocytes (DOK) were transformed into oral carcinoma cells (DOK-TC), and assessed the effects of inhibiting PORCN with the C59 inhibitor. Similarly, an in vivo model of oral carcinogenesis and ex vivo samples derived from patients diagnosed with oral dysplasia and OSCC were treated with C59.
Results:
Both in vitro and ex vivo oral carcinogenesis approaches revealed decreased levels of nuclear β-catenin and Wnt3a, as observed by immunofluorescence and IHC analyses. Consistently, reduced protein and mRNA levels of survivin were observed after treatment with C59. Functionally, treatment with C59 in vitro resulted in diminished cell migration, viability, and invasion. Finally, by using an in vivo model of oral carcinogenesis, we found that treatment with C59 prevented the development of OSCC by reducing the size and number of oral tumor lesions.
Conclusions:
The inhibition of Wnt ligand secretion with C59 represents a feasible treatment to prevent the progression of early oral lesions toward OSCC.
Data from Tumor Volume Growth Rates and Doubling Times during Active Surveillance of IDH-mutant Low-Grade Glioma
Authors: Bhatia Ankush , Moreno Raquel , Reiner Anne S. , Nandakumar Subhiksha , Walch Henry S. , Thomas Teena M. , Nicklin Philip J. , Choi Ye , Skakodub Anna , Malani Rachna , Prabhakaran Vivek , Tiwari Pallavi , Diaz Maria , Panageas Katherine S. , Mellinghoff Ingo K. , Bale Tejus A. , Young Robert J.
Published: January 2024

AbstractPurpose:
Isocitrate dehydrogenase–mutant (IDH-mt) gliomas are incurable primary brain tumors characterized by a slow-growing phase over several years followed by a rapid-growing malignant phase. We hypothesized that tumor volume growth rate (TVGR) on MRI may act as an earlier measure of clinical benefit during the active surveillance period.
Experimental Design:
We integrated three-dimensional volumetric measurements with clinical, radiologic, and molecular data in a retrospective cohort of IDH-mt gliomas that were observed after surgical resection in order to understand tumor growth kinetics and the impact of molecular genetics.
Results:
Using log-linear mixed modeling, the entire cohort (n = 128) had a continuous %TVGR per 6 months of 10.46% [95% confidence interval (CI), 9.11%–11.83%] and a doubling time of 3.5 years (95% CI, 3.10–3.98). High molecular grade IDH-mt gliomas, defined by the presence of homozygous deletion of CDKN2A/B, had %TVGR per 6 months of 19.17% (95% CI, 15.57%–22.89%) which was significantly different from low molecular grade IDH-mt gliomas with a growth rate per 6 months of 9.54% (95% CI, 7.32%–11.80%; P < 0.0001). Using joint modeling to comodel the longitudinal course of TVGR and overall survival, we found each one natural logarithm tumor volume increase resulted in more than a 3-fold increase in risk of death (HR = 3.83; 95% CI, 2.32–6.30; P < 0.0001).
Conclusions:
TVGR may be used as an earlier measure of clinical benefit and correlates well with the WHO 2021 molecular classification of gliomas and survival. Incorporation of TVGR as a surrogate endpoint into future prospective studies of IDH-mt gliomas may accelerate drug development.
Data from PET/CT Biomarkers Enable Risk Stratification of Patients with Relapsed/Refractory Diffuse Large B-cell Lymphoma Enrolled in the LOTIS-2 Clinical Trial
Authors: Alderuccio Juan Pablo , Reis Isildinha M. , Hamadani Mehdi , Nachiappan Muthiah , Leslom Salman , Kahl Brad S. , Ai Weiyun Z. , Radford John , Solh Melhem , Ardeshna Kirit M. , Hess Brian T. , Lunning Matthew A. , Zinzani Pier Luigi , Stathis Anastasios , Carlo-Stella Carmelo , Lossos Izidore S. , Caimi Paolo F. , Han Sunwoo , Yang Fei , Kuker Russ A. , Moskowitz Craig H.
Published: January 2024

AbstractPurpose:
Significant progress has occurred in developing quantitative PET/CT biomarkers in diffuse large B-cell lymphoma (DLBCL). Total metabolic tumor volume (MTV) is the most extensively studied, enabling assessment of FDG-avid tumor burden associated with outcomes. However, prior studies evaluated the outcome of cytotoxic chemotherapy or chimeric antigen receptor T-cell therapy without data on recently approved FDA agents. Therefore, we aimed to assess the prognosis of PET/CT biomarkers in patients treated with loncastuximab tesirine.
Experimental Design:
We centrally reviewed screening PET/CT scans of patients with relapsed/refractory DLBCL enrolled in the LOTIS-2 (NCT03589469) study. MTV was obtained by computing individual volumes using the SUV ≥4.0 threshold. Other PET/CT metrics, clinical factors, and the International Metabolic Prognostic Index (IMPI) were evaluated. Logistic regression was used to assess the association between biomarkers and treatment response. Cox regression was used to determine the effect of biomarkers on time-to-event outcomes. We estimated biomarker prediction as continuous and binary variables defined by cutoff points.
Results:
Across 138 patients included in this study, MTV with a cutoff point of 96 mL was the biomarker associated with the highest predictive performance in univariable and multivariable models to predict failure to achieve complete metabolic response (OR, 5.42; P = 0.002), progression-free survival (HR, 2.68; P = 0.002), and overall survival (HR, 3.09; P < 0.0001). IMPI demonstrated an appropriate performance, however, not better than MTV alone.
Conclusions:
Pretreatment MTV demonstrated robust risk stratification, with those patients demonstrating high MTV achieving lower responses and survival to loncastuximab tesirine in relapsed/refractory DLBCL.
Data from Comprehensive DNA Methylation Profiling of Medullary Thyroid Carcinoma: Molecular Classification, Potential Therapeutic Target, and Classifier System
Authors: Shen Cenkai , Shi Xiao , Wen Duo , Zhang Yuqing , Du Yuxin , Zhang Yu , Ma Ben , Tang Haitao , Yin Min , Huang Naisi , Liao Tian , Zhang Ting-Ting , Kong Chang’e , Wei Wenjun , Ji Qinghai , Wang Yu
Published: January 2024

AbstractPurpose:
Medullary thyroid carcinoma (MTC) presents a distinct biological context from other thyroid cancers due to its specific cellular origin. This heterogeneous and rare tumor has a high prevalence of advanced diseases, making it crucial to address the limited therapeutic options and enhance complex clinical management. Given the high clinical accessibility of methylation information, we construct the largest MTC methylation cohort to date.
Experimental Design:
Seventy-eight fresh-frozen MTC samples constituted our methylation cohort. The comprehensive study process incorporated machine learning, statistical analysis, and in vitro experiments.
Results:
Our study pioneered the identification of a three-class clustering system for risk stratification, exhibiting pronounced epigenomic heterogeneity. The elevated overall methylation status in MTC-B, combined with the “mutual exclusivity” of hypomethylated sites displayed by MTC-A and MTC-C, distinctively characterized the MTC-specific methylation pattern. Integrating with the transcriptome, we further depicted the features of these three clusters to scrutinize biological properties. Several MTC-specific aberrant DNA methylation events were emphasized in our study. NNAT expression was found to be notably reduced in poor-prognostic MTC-C, with its promoter region overlapping with an upregulated differentially methylated region. In vitro experiments further affirmed NNAT's therapeutic potential. Moreover, we built an elastic-net logistic regression model with a relatively high AUC encompassing 68 probes, intended for future validation and systematic clinical application.
Conclusions:
Conducting research on diseases with low incidence poses significant challenges, and we provide a robust resource and comprehensive research framework to assist in ongoing MTC case inclusion and facilitate in-depth dissection of its molecular biological features.
Data from Proteomic Profiling of Advanced Melanoma Patients to Predict Therapeutic Response to Anti-PD-1 Therapy
Authors: Zila Nina , Eichhoff Ossia M. , Steiner Irene , Mohr Thomas , Bileck Andrea , Cheng Phil F. , Leitner Alexander , Gillet Ludovic , Sajic Tatjana , Goetze Sandra , Friedrich Betty , Bortel Patricia , Strobl Johanna , Reitermaier René , Hogan Sabrina A. , Martínez Gómez Julia M. , Staeger Ramon , Tuchmann Felix , Peters Sophie , Stary Georg , Kuttke Mario , Elbe-Bürger Adelheid , Hoeller Christoph , Kunstfeld Rainer , Weninger Wolfgang , Wollscheid Bernd , Dummer Reinhard , French Lars E. , Gerner Christopher , Aebersold Ruedi , Levesque Mitchell P. , Paulitschke Verena
Published: January 2024

AbstractPurpose:
Despite high clinical need, there are no biomarkers that accurately predict the response of patients with metastatic melanoma to anti-PD-1 therapy.
Experimental Design:
In this multicenter study, we applied protein depletion and enrichment methods prior to various proteomic techniques to analyze a serum discovery cohort (n = 56) and three independent serum validation cohorts (n = 80, n = 12, n = 17). Further validation analyses by literature and survival analysis followed.
Results:
We identified several significantly regulated proteins as well as biological processes such as neutrophil degranulation, cell–substrate adhesion, and extracellular matrix organization. Analysis of the three independent serum validation cohorts confirmed the significant differences between responders (R) and nonresponders (NR) observed in the initial discovery cohort. In addition, literature-based validation highlighted 30 markers overlapping with previously published signatures. Survival analysis using the TCGA database showed that overexpression of 17 of the markers we identified correlated with lower overall survival in patients with melanoma.
Conclusions:
Ultimately, this multilayered serum analysis led to a potential marker signature with 10 key markers significantly altered in at least two independent serum cohorts: CRP, LYVE1, SAA2, C1RL, CFHR3, LBP, LDHB, S100A8, S100A9, and SAA1, which will serve as the basis for further investigation. In addition to patient serum, we analyzed primary melanoma tumor cells from NR and found a potential marker signature with four key markers: LAMC1, PXDN, SERPINE1, and VCAN.
Data from Risk Factors Associated with Durable Progression-Free Survival in Patients with Relapsed or Refractory Multiple Myeloma Treated with Anti-BCMA CAR T-cell Therapy
Authors: Zhang Mingming , Zhou Linghui , Zhao Houli , Zhang Yanlei , Wei Guoqing , Hong Ruimin , Wu Wenjun , Xu Huijun , Wang Linqin , Ni Fang , Cui Jiazhen , Peng Shuixiu , Huang Chih-Hua , Chang Alex H. , Hu Yongxian , Huang He
Published: January 2024

AbstractPurpose:
B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy results in high remission rates in patients with relapsed/refractory (R/R) multiple myeloma. However, the factors associated with prognosis following CAR T-cell therapy are unknown.
Patients and Methods:
Between July 1, 2018 and July 31, 2020, 61 patients with R/R multiple myeloma received anti-BCMA CAR T-cell therapy (Chictr.org number, ChiCTR1800017404). Step-wise multivariate Cox regression and competing risk analyses were conducted to identify poor prognosis–associated risk factors.
Results:
Sixty patients (98.4%) experienced cytokine release syndrome (CRS), including 33, 23, and 4 cases of CRS grades 1 to 2, 3, and 4, respectively. The objective response rate (ORR) was 98.3%, and the complete remission (CR) rate was 70.3%. With a median follow-up period of 21.1 months, the 1-year overall survival (OS) and progression-free survival (PFS) rates were 78.0% and 50.2%, respectively. The median PFS was 12.7 months. Cox modeling revealed that poor PFS was associated with extramedullary disease [HR = 2.59, 95% confidence interval (95% CI) = 1.29–5.21, P = 0.008], light chain multiple myeloma (HR = 2.53, 95% CI = 1.03–5.97, P = 0.035), high-risk cytogenetics (HR = 2.80, 95% CI = 1.27–6.14, P = 0.01), and prior treatment with more than 3 therapeutic lines (HR = 3.14, 95% CI = 1.34–7.34, P = 0.008). Among the 41 CR cases, competing risk analyses demonstrated higher relapse predispositions in those with extramedullary disease (HR = 4.51, 95% CI = 1.86–10.9, P = 0.001), light chain multiple myeloma (HR = 4.89, 95% CI = 1.52 – 15.7, P = 0.008), or high-risk cytogenetics (HR = 5.09, 95% CI = 1.63–15.9, P = 0.005).
Conclusions:
Anti-BCMA CAR T-cell therapy is safe and effective for R/R multiple myeloma. For patients with high-risk factors, improvements to extend remission and more specific individualized therapies are needed.
Data from Nanoliposomal Short-Chain Ceramide Inhibits Agonist-Dependent Translocation of Neurotensin Receptor 1 to Structured Membrane Microdomains in Breast Cancer Cells
Authors: Heakal Yasser , Kester Mark
Published: January 2024

Abstract
Neurotensin (NTS) receptor 1 (NTSR1) is a G protein–coupled receptor that has been recently identified as a mediator of tumorigenicity and metastasis. NTSR1, as well as its endogenous ligand, NTS, are coexpressed in several breast cancer cell lines and breast cancer tumor samples but not in normal breast tissue. We have previously published that ceramide mimetics could inhibit breast cancer growth in vitro and in vivo. Thus, understanding the biochemical and biophysical regulation of NTSR1 by ceramide can help further define NTSR1 as a novel target in breast cancer. Our results show that nanoliposomal formulations of ceramide inhibit NTSR1-mediated MDA-MB-231 breast cancer progression (mitogenesis, migration, and matrix metalloproteinase-9 activity). In addition, liposomal ceramide inhibited NTSR1-mediated, but not phorbol 12-myristate 13-acetate–mediated, activation of the mitogen-activated protein kinase pathway. Mechanistically, nanoliposomal short-chain ceramide reduces NTSR1 interaction with Gαq/11 subunits within structured membrane microdomains, consistent with diminished NTS-induced translocation of NTSR1 into membrane microdomains. Collectively, our findings suggest that exogenous short-chain ceramide has the potential to be used as an adjuvant therapy to inhibit NTS-dependent breast cancer progression. (Mol Cancer Res 2009;7(5):724–34)
Data from Activation of p38 Mitogen-Activated Protein Kinase Is Required for Death Receptor–Independent Caspase-8 Activation and Cell Death in Response to Sphingosine
Authors: Yoon Chang-Hwan , Kim Min-Jung , Park Moon-Taek , Byun Joo-Yun , Choi Young-Hyun , Yoo Hwan-Soo , Lee Yong-Moon , Hyun Jin-Won , Lee Su-Jae
Published: January 2024

Abstract
Sphingosine induces activation of multiple signaling pathways that play critical roles in controlling cell death. However, the precise molecular mechanism of cell death induced by sphingosine remains to be clarified. In this study, we show that sphingosine induces death receptor–independent caspase-8 activation and apoptotic cell death via p38 mitogen-activated protein kinase (MAPK) activation and that suppression of the MAPK/extracellular signal–regulated kinase (ERK) kinase/ERK pathway by protein phosphatase 2A (PP2A) is required for p38 MAPK activation. Treatment of cells with sphingosine induced suppression of ERK and activation of p38 MAPK. Inhibition of p38 MAPK led to the marked suppression of death receptor–independent caspase-8 activation and subsequent cell death induced by sphingosine. Interestingly, pretreatment with phorbol 12-myristate 13-acetate or transfection of MAPK/ERK kinase/ERK resulting in ERK activation completely attenuated sphingosine-induced p38 MAPK activation. PP2A activity was additionally elevated on sphingosine treatment. Small interfering RNA targeting of PP2A effectively attenuated sphingosine-induced p38 MAPK activation through restoration of ERK activity, suggesting PP2A-mediated opposing regulation of ERK and p38 MAPK. Our findings clearly imply that activation of p38 MAPK promotes death receptor–independent activation of caspase-8 and apoptotic cell death pathways, thus providing a novel cellular mechanism for the anticancer activity of sphingolipid metabolites. (Mol Cancer Res 2009;7(3):361–70)
Data from Yin Yang 1 Modulates Taxane Response in Epithelial Ovarian Cancer
Authors: Matsumura Noriomi , Huang Zhiqing , Baba Tsukasa , Lee Paula S. , Barnett Jason C. , Mori Seiichi , Chang Jeffrey T. , Kuo Wen-Lin , Gusberg Alison H. , Whitaker Regina S. , Gray Joe W. , Fujii Shingo , Berchuck Andrew , Murphy Susan K.
Published: January 2024

Abstract
Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein, we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary serous epithelial ovarian cancer and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using small interfering RNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in ovarian cancer and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule-stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA cross-linking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1 knockdown in ovarian cancer cell lines results in inhibition of anchorage-independent growth, motility, and proliferation but also increases resistance to taxanes, with no effect on cisplatin sensitivity. These results, together with the prior demonstration of augmentation of microtubule-related genes by E2F3, suggest that enhanced taxane sensitivity in tumors with high YY1/E2F activity may be mediated by modulation of putative target genes with microtubule function. (Mol Cancer Res 2009;7(2):210–20)
Data from Epigenetic Down-Regulation of ARF Expression Is a Selection Step in Immortalization of Human Fibroblasts by c-Myc
Authors: Benanti Jennifer A. , Wang Myra L. , Myers Hadley E. , Robinson Kristin L. , Grandori Carla , Galloway Denise A.
Published: January 2024

Abstract
The transcription factor c-Myc is implicated in the pathogenesis of many cancers. Among the multiple functions of c-Myc, activation of hTert and other genes involved in cellular life span contributes to its role as an oncogene. However, the ability of c-Myc to directly immortalize human cells remains controversial. We show here that overexpression of c-Myc reproducibly immortalizes freshly isolated human foreskin fibroblasts. c-Myc–immortalized cells displayed no gross karyotypic abnormalities but consisted of an oligoclonal population, suggesting that additional events cooperated to achieve immortalization. Levels of p53 and p16 were increased, but both p53-dependent DNA damage response and growth arrest in response to p16 overexpression remained intact. A marked decrease in expression of the tumor suppressor ARF occurred in several independently established c-Myc–immortalized cell lines. Methylation-specific PCR showed that the ARF gene was methylated in immortalized but not early-passage c-Myc cells, whereas p16 was unmethylated in both cell populations. Restoration of ARF expression by treatment with a demethylating agent or overexpression by a retroviral vector coincided with inhibition of proliferation and senescence of c-Myc–immortalized cells. Our findings predict that epigenetic events play a significant role in human tumors that express high levels of c-Myc. (Mol Cancer Res 2007;5(11):1181–9)