bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Data from LSD1 Inhibition Disrupts Super-Enhancer–Driven Oncogenic Transcriptional Programs in Castration-Resistant Prostate Cancer
Authors: Li Muqing , Liu Mingyu , Han Wanting , Wang Zifeng , Han Dong , Patalano Susan , Macoska Jill A. , Balk Steven P. , He Housheng Hansen , Corey Eva , Gao Shuai , Cai Changmeng
Published: May 2023

Supplementary data
Figure S1 from BRCA2 Germline Mutations Identify Gastric Cancers Responsive to PARP Inhibitors
Authors: Petrelli Annalisa , Rizzolio Sabrina , Pietrantonio Filippo , Bellomo Sara E. , Benelli Matteo , De Cecco Loris , Romagnoli Dario , Berrino Enrico , Orrù Claudia , Ribisi Salvatore , Moya-Rull Daniel , Migliore Cristina , Conticelli Daniela , Maina Irene M. , Puliga Elisabetta , Serra Violeta , Pellegrino Benedetta , Llop-Guevara Alba , Musolino Antonino , Siena Salvatore , Sartore-Bianchi Andrea , Prisciandaro Michele , Morano Federica , Antista Maria , Fumagalli Uberto , De Manzoni Giovanni , Degiuli Maurizio , Baiocchi Gian Luca , Amisano Marco F. , Ferrero Alessandro , Marchiò Caterina , Corso Simona , Giordano Silvia
Published: May 2023

HR gene mutations in GEA models used in in vitro and in vivo experiments.
Supplementary Fig. S8 from Single-Cell Spatial Analysis Identifies Regulators of Brain Tumor–Initiating Cells
Authors: Mirzaei Reza , D'Mello Charlotte , Liu Marina , Nikolic Ana , Kumar Mehul , Visser Frank , Bose Pinaki , Gallo Marco , Yong V. Wee
Published: May 2023

Additional analysis of in vitro proliferative effects of biglycan.
Supplementary Fig. S2 from Single-Cell Spatial Analysis Identifies Regulators of Brain Tumor–Initiating Cells
Authors: Mirzaei Reza , D'Mello Charlotte , Liu Marina , Nikolic Ana , Kumar Mehul , Visser Frank , Bose Pinaki , Gallo Marco , Yong V. Wee
Published: May 2023

Spatial gene expression of ECM molecules in mouse brain tumors.
Data from Inhibition of ACAA1 Restrains Proliferation and Potentiates the Response to CDK4/6 Inhibitors in Triple-Negative Breast Cancer
Authors: Peng Wen-Ting , Jin Xi , Xu Xiao-En , Yang Yun-Song , Ma Ding , Shao Zhi-Ming , Jiang Yi-Zhou
Published: May 2023

Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with unfavorable outcomes. Developing therapeutic targets for TNBC remains a challenge. Here, we identified that acetyl-CoA acyltransferase 1 (ACAA1) is highly expressed in the luminal androgen receptor (LAR) subtype of TNBC compared with adjacent normal tissues in our TNBC proteomics dataset. Inhibition of ACAA1 restrained TNBC proliferation and potentiated the response to the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor abemaciclib. Mechanistically, ACAA1 interacted with CDK4, and the inhibition of ACAA1 blocked RB transcriptional corepressor 1 (RB1) phosphorylation, resulting in G1–S cell-cycle arrest. Importantly, trimetazidine, a traditional drug for ischemic heart disease, caused a decrease in ACAA1 protein levels and enhanced the efficacy of abemaciclib in preclinical TNBC models. In conclusion, this study identifies that ACAA1 is a therapeutic target in TNBC and suggests the combination of trimetazidine and abemaciclib could be beneficial for ACAA1-high TNBCs.
Significance:
ACAA1 is highly expressed in TNBC, serving as a potential therapeutic target in ACAA1-high tumors and a predictive biomarker of resistance to CDK4/6 inhibitors for RB1-proficient patients.
Data from ASS1-Mediated Reductive Carboxylation of Cytosolic Glutamine Confers Ferroptosis Resistance in Cancer Cells
Authors: Hu Qiangsheng , Dai Jie , Zhang Zheng , Yu Huansha , Zhang Jing , Zhu Xinsheng , Qin Yi , Zhang Lele , Zhang Peng
Published: May 2023

Abstract
Induction of ferroptosis, a recently defined form of nonapoptotic cell death caused by iron-dependent lipid peroxidation, has emerged as an anticancer strategy. Erastin is a ferroptosis activator that promotes cell death that not only depends on the depletion of cellular cysteine but also relies on mitochondrial oxidative metabolism of glutamine. Here, we demonstrate that ASS1, a key enzyme involved in the urea cycle, plays a crucial role in ferroptosis resistance. Loss of ASS1 increased the sensitivity of non–small cell lung cancer (NSCLC) cells to erastin in vitro and decreased tumor growth in vivo. Metabolomics analysis with stable isotope-labeled glutamine showed that ASS1 promotes reductive carboxylation of cytosolic glutamine and compromises the oxidative tricarboxylic acid cycle from glutamine anaplerosis, reducing mitochondrial-derived lipid reactive oxygen species. Moreover, transcriptome sequencing showed that ASS1 activates the mTORC1–SREBP1–SCD5 axis to promote de novo monounsaturated fatty acid synthesis by using acetyl-CoA derived from the glutamine reductive pathway. Treating ASS1-deficient NSCLC cells with erastin combined with arginine deprivation significantly enhanced cell death compared with either treatment alone. Collectively, these results reveal a previously unknown regulatory role of ASS1 in ferroptosis resistance and provide a potential therapeutic target for ASS1-deficient NSCLC.
Significance:
ASS1 promotes reductive carboxylation of glutamine and confers ferroptosis resistance, providing multiple treatment options for ASS1-deficient non–small cell lung cancer.
Data from Microenvironment-Driven Dynamic Chromatin Changes in Glioblastoma Recapitulate Early Neural Development at Single-Cell Resolution
Authors: Pine Allison R. , Cirigliano Stefano M. , Singhania Richa , Nicholson James , da Silva Bárbara , Leslie Christina S. , Fine Howard A.
Published: May 2023

Abstract
The tumor microenvironment is necessary for recapitulating the intratumoral heterogeneity and cell state plasticity found in human primary glioblastoma (GBM). Conventional models do not accurately recapitulate the spectrum of GBM cellular states, hindering elucidation of the underlying transcriptional regulation of these states. Using our glioblastoma cerebral organoid model, we profiled the chromatin accessibility of 28,040 single cells in five patient-derived glioma stem cell lines. Integration of paired epigenomes and transcriptomes within the context of tumor-normal host cell interactions was used to probe the gene-regulatory networks underlying individual GBM cellular states in a way not readily possible in other in vitro models. These analyses identified the epigenetic underpinnings of GBM cellular states and characterized dynamic chromatin changes reminiscent of early neural development that underlie GBM cell state transitions. Despite large differences between tumors, a shared cellular compartment made up of neural progenitor-like cells and outer radial glia–like cells was observed. Together, these results shed light on the transcriptional regulation program in GBM and offer novel therapeutic targets across a broad range of genetically heterogenous GBMs.
Significance:
Single-cell analyses elucidate the chromatin landscape and transcriptional regulation of glioblastoma cellular states and identify a radial glia–like population, providing potential targets to disrupt cell states and improve therapeutic efficacy.
Retinol Saturase Mediates Retinoid Metabolism to Impair a Ferroptosis Defense System in Cancer Cells
Authors: Bi Guoshu , Liang Jiaqi , Shan Guangyao , Bian Yunyi , Chen Zhencong , Huang Yiwei , Lu Tao , Li Ming , Besskaya Valeria , Zhao Mengnan , Fan Hong , Wang Qun , Gan Boyi , Zhan Cheng
Published: May 2023

Ferroptosis is an iron-dependent form of regulated cell death induced by the lethal overload of lipid peroxides in cellular membranes. In recent years, modulating ferroptosis has gained attention as a potential therapeutic approach for tumor suppression. In the current study, retinol saturase (RETSAT) was identified as a significant ferroptosis mediator using a publicly accessible CRISPR/Cas9 screening dataset. RETSAT depletion protected tumor cells from lipid peroxidation and subsequent cell death triggered by various ferroptosis inducers. Furthermore, exogenous supplementation with retinoids, including retinol (the substrate of RETSAT) and its derivatives retinal and retinoic acid, also suppressed ferroptosis, whereas the product of RETSAT, 13, 14-dihydroretinol, failed to do so. As effective radical-trapping antioxidant, retinoids protected the lipid membrane from autoxidation and subsequent fragmentation, thus terminating the cascade of ferroptosis. Pseudotargeted lipidomic analysis identified an association between retinoid regulation of ferroptosis and lipid metabolism. Retinoic acid, but not 13, 14-dihydroretinoic acid, interacted with its nuclear receptor and activated transcription of stearoyl-CoA desaturase, which introduces the first double bond into saturated fatty acid and thus catalyzes the generation of monounsaturated fatty acid, a known ferroptosis suppressor. Therefore, RETSAT promotes ferroptosis by transforming retinol to 13, 14-dihydroretinol, thereby turning a strong anti-ferroptosis regulator into a relatively weak one.

Significance:

Retinoids have ferroptosis-protective properties and can be metabolized by RETSAT to promote ferroptosis, suggesting the possibility of targeting retinoid metabolism in cancer as a treatment strategy to trigger ferroptosis.
Development and Demonstration of Tobacco Treatment Measures for Cancer Registries: Novel Metrics for Quality Improvement
Authors: Hutcheson Tresza D. , Metcalf Tim , Ellerbeck Edward F. , Cox Lisa Sanderson , Hu Jinxiang , Chen Xi , Richter Kimber P.
Published: May 2023

Background:

Individuals undergoing cancer treatment have better outcomes when they discontinue tobacco use. Few cancer centers systematically provide evidence-based cessation services. As part of a national quality improvement initiative [Cancer Center Cessation Initiative (C3i)], we collaborated with our cancer registry to develop and implement two tobacco treatment metrics for tracking the provision of behavioral support and pharmacotherapy.

Methods:

Post-development, the tobacco treatment metrics were integrated into the registry for all future patients. We used means and frequencies to summarize tobacco treatment for cases treated between 2017 and 2019, coinciding with the timeframe of C3i participation.

Results:

Of 17,735 cancer cases reviewed, both measures were captured on 17,654 (99.5%) of patients, with 3,091 (17.4%) identified as users of tobacco. Across the 3 years, 557 (18%) of individuals who used tobacco received either tobacco cessation pharmacotherapy or behavioral support; with 478 (15.5%) receiving behavioral counseling, 352 (11.4%) receiving pharmacotherapy, and 273 (8.8%) receiving both—considered gold standard care. Tobacco treatment varied substantially across cancer types. The odds of receiving gold standard care were 2.37 times greater in 2019 compared with 2017. (OR, 2.37; 95% confidence interval, 1.63–3.46; P < 0.0001).

Conclusions:

The new metrics demonstrated high completion rates and their potential to track quality improvement efforts over time. They identified suboptimal treatment reach, but a potential increase in treatment over time and greater treatment among tobacco-related versus nontobacco-related cancers.

Impact:

Continued tobacco use worsens cancer care outcomes. Integrating measures into cancer registries is a viable option for tracking tobacco treatment and cessation in the context of cancer care.
Climate Change and Cancer
Authors: Nogueira Leticia M. , Crane Tracy E. , Ortiz Ana P. , D'Angelo Heather , Neta Gila
Published: May 2023

Climate change, the greatest threat to human health of our time, has implications for cancer control efforts throughout the cancer care continuum. The direct and indirect impacts of climate change on cancer risk, access to care, and outcomes are numerous and compounding, yet many oncology professionals might not be familiar with the strong connection between climate change and cancer. Thus, to increase awareness of this topic among cancer researchers, practitioners, and other professionals, this commentary discusses the links between climate change and cancer prevention and control, provides examples of adaptation and mitigation efforts, and describes opportunities and resources for future research.
Supplementary Figure S1 from Randomized Phase II Cabazitaxel Dose Individualization and Neutropenia Prevention Trial in Patients with Metastatic Castration-Resistant Prostate Cancer
Authors: Omlin Aurelius , Cathomas Richard , von Amsberg Gunhild , Reuter Christoph , Feyerabend Susan , Loidl Wolfgang , Boegemann Martin , Lorch Anja , Heidenreich Axel , Tsaur Igor , Larcher-Senn Julian , Buck Stefan A.J. , Mathijssen Ron H.J. , Jaehde Ulrich , Gillessen Silke , Joerger Markus
Published: May 2023

CONSORT Diagram
Figure S9 from Treatment of Prostate Cancer with CD46-targeted 225Ac Alpha Particle Radioimmunotherapy
Authors: Bidkar Anil P. , Wang Sinan , Bobba Kondapa Naidu , Chan Emily , Bidlingmaier Scott , Egusa Emily A. , Peter Robin , Ali Umama , Meher Niranjan , Wadhwa Anju , Dhrona Suchi , Dasari Chandrashekhar , Beckford-Vera Denis , Su Yang , Tang Ryan , Zhang Li , He Jiang , Wilson David M. , Aggarwal Rahul , VanBrocklin Henry F. , Seo Youngho , Chou Jonathan , Liu Bin , Flavell Robert R.
Published: May 2023

Figure S9: Histology evaluation of the healthy tissues for long-term (117 days) toxicity analysis. Hematoxylin and Eosin (H&E) staining of spleen, liver, lungs, heart, and bone samples show no toxicity at 0.25 µCi or 0.5 µCi doses of [225Ac]DOTA-YS5. Scale bar: 20 µm
Supplementary Table 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: May 2023

IC50 values of PI3K isoform inhibitors used. Duvelisib5, IPI-3063 (PI3K-d inhibitor)5, IPI-549 (PI3K-g inhibitor used in vitro)50, IPI-5243 (PI3K-g inhibitor used in vivo).
Figure S4 from Treatment of Prostate Cancer with CD46-targeted 225Ac Alpha Particle Radioimmunotherapy
Authors: Bidkar Anil P. , Wang Sinan , Bobba Kondapa Naidu , Chan Emily , Bidlingmaier Scott , Egusa Emily A. , Peter Robin , Ali Umama , Meher Niranjan , Wadhwa Anju , Dhrona Suchi , Dasari Chandrashekhar , Beckford-Vera Denis , Su Yang , Tang Ryan , Zhang Li , He Jiang , Wilson David M. , Aggarwal Rahul , VanBrocklin Henry F. , Seo Youngho , Chou Jonathan , Liu Bin , Flavell Robert R.
Published: May 2023

Figure S4: Gamma energy spectra of the tumor, blood, kidneys, and bone showing the intensities of the 213Bi and 221Fr peaks. As compared to the equilibrium gamma energy spectra of [225Ac]DOTA-YS5, increased intensity of the 213Bi was observed in kidney samples.
Supplementary Figure S3 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: May 2023

Distinct actions of PI3K-δ and PI3K-γ on numbers of immune cells in CLL.
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: May 2023

Effects of PI3K-gi, PI3K-di on the proliferation and migration of CLL-derived T cells.
Figure S11 from Treatment of Prostate Cancer with CD46-targeted 225Ac Alpha Particle Radioimmunotherapy
Authors: Bidkar Anil P. , Wang Sinan , Bobba Kondapa Naidu , Chan Emily , Bidlingmaier Scott , Egusa Emily A. , Peter Robin , Ali Umama , Meher Niranjan , Wadhwa Anju , Dhrona Suchi , Dasari Chandrashekhar , Beckford-Vera Denis , Su Yang , Tang Ryan , Zhang Li , He Jiang , Wilson David M. , Aggarwal Rahul , VanBrocklin Henry F. , Seo Youngho , Chou Jonathan , Liu Bin , Flavell Robert R.
Published: May 2023

Figure S11: Antitumor activity of [225Ac]DOTA-YS5 in subcutaneous DU145 tumors in nude mice. Tumor volume, survival analysis, and weight measurements after the injections of [225Ac]DOTA-YS5 in DU145 xenografts (n=6).
Figure S10 from Treatment of Prostate Cancer with CD46-targeted 225Ac Alpha Particle Radioimmunotherapy
Authors: Bidkar Anil P. , Wang Sinan , Bobba Kondapa Naidu , Chan Emily , Bidlingmaier Scott , Egusa Emily A. , Peter Robin , Ali Umama , Meher Niranjan , Wadhwa Anju , Dhrona Suchi , Dasari Chandrashekhar , Beckford-Vera Denis , Su Yang , Tang Ryan , Zhang Li , He Jiang , Wilson David M. , Aggarwal Rahul , VanBrocklin Henry F. , Seo Youngho , Chou Jonathan , Liu Bin , Flavell Robert R.
Published: May 2023

Figure S10: Tumor volumes, overall survival, and body weights for the saline and fractionated dose (0.125 µCi x 3) injections in 22Rv1 xenografts. Results show delayed tumor growth and improved survival without the significant toxicity from fractionated dose treatment (n=10).
Supplementary Table S2 from Randomized Trial of Tepotinib Plus Gefitinib versus Chemotherapy in EGFR-Mutant NSCLC with EGFR Inhibitor Resistance Due to MET Amplification: INSIGHT Final Analysis
Authors: Liam Chong Kin , Ahmad Azura Rozila , Hsia Te-Chun , Zhou Jianying , Kim Dong-Wan , Soo Ross Andrew , Cheng Ying , Lu Shun , Shin Sang Won , Yang James Chih-Hsin , Zhang Yiping , Zhao Jun , Berghoff Karin , Bruns Rolf , Johne Andreas , Wu Yi-Long
Published: May 2023

Representativeness of study population
Suppl Fig 3 from Targeting the Inducible T-cell Costimulator (ICOS) in Patients with Relapsed/Refractory T-follicular Helper Phenotype Peripheral T-cell and Angioimmunoblastic T-cell Lymphoma
Authors: Chavez Julio C. , Foss Francine M. , William Basem M. , Brammer Jonathan E. , Smith Sonali M. , Prica Anca , Zain Jasmine M. , Tuscano Joseph M. , Shah Harsh , Mehta-Shah Neha , Geethakumari Praveen Ramakrishnan , Wang Ben X. , Zantinge Stephanie , Wang Lisa , Zhang Ling , Boutrin Anmarie , Zhao Weiguang , Cheng Lily , Standifer Nathan , Hewitt Lisa , Enowtambong Enowmpey , Shao Weiping , Sharma Shringi , Carlesso Gianluca , Moscow Jeffrey A. , Siu Lillian L.
Published: May 2023

Supplemental Figure 3. Representative baseline pre-treatment tumor specimen of a patient with AITL (H&E, ICOS staining and CD3 staining by IHC)
Suppl Fig 1 from Targeting the Inducible T-cell Costimulator (ICOS) in Patients with Relapsed/Refractory T-follicular Helper Phenotype Peripheral T-cell and Angioimmunoblastic T-cell Lymphoma
Authors: Chavez Julio C. , Foss Francine M. , William Basem M. , Brammer Jonathan E. , Smith Sonali M. , Prica Anca , Zain Jasmine M. , Tuscano Joseph M. , Shah Harsh , Mehta-Shah Neha , Geethakumari Praveen Ramakrishnan , Wang Ben X. , Zantinge Stephanie , Wang Lisa , Zhang Ling , Boutrin Anmarie , Zhao Weiguang , Cheng Lily , Standifer Nathan , Hewitt Lisa , Enowtambong Enowmpey , Shao Weiping , Sharma Shringi , Carlesso Gianluca , Moscow Jeffrey A. , Siu Lillian L.
Published: May 2023

Supplemental Figure 1. CD4 count recovery after end of treatment (by local site collection)
Table S4 from PSMA-positive Circulating Tumor Cell Detection and Outcomes with Abiraterone or Enzalutamide Treatment in Men with Metastatic Castrate-resistant Prostate Cancer
Authors: Gupta Santosh , Halabi Susan , Yang Qian , Roy Akash , Tubbs Alisa , Gore Yamini , George Daniel J. , Nanus David M. , Antonarakis Emmanuel S. , Danila Daniel C. , Szmulewitz Russell Z. , Wenstrup Richard , Armstrong Andrew J.
Published: May 2023

CTC biomarker group incidence by PSMA optimal cutoff (AR-v7, chromosomal instability (CIN), and neuroendocrine (NE) at baseline (N=97) and progression (N=57).
Figure S4 from PSMA-positive Circulating Tumor Cell Detection and Outcomes with Abiraterone or Enzalutamide Treatment in Men with Metastatic Castrate-resistant Prostate Cancer
Authors: Gupta Santosh , Halabi Susan , Yang Qian , Roy Akash , Tubbs Alisa , Gore Yamini , George Daniel J. , Nanus David M. , Antonarakis Emmanuel S. , Danila Daniel C. , Szmulewitz Russell Z. , Wenstrup Richard , Armstrong Andrew J.
Published: May 2023

Percent PSMA expression positivity (PSMA+CTC x 100/ Traditional CTC) across PSMA+ Neuroendocrine Phenotype (NE) - and PSMA+ NE+ baseline (A) and progression (B) samples.
Figure S5 from Quiescent Ovarian Cancer Cells Secrete Follistatin to Induce Chemotherapy Resistance in Surrounding Cells in Response to Chemotherapy
Authors: Cole Alexander J. , Panesso-Gómez Santiago , Shah Jaynish S. , Ebai Tonge , Jiang Qi , Gumusoglu-Acar Ece , Bello Maya G. , Vlad Anda , Modugno Francesmary , Edwards Robert P. , Buckanovich Ronald J.
Published: May 2023

Supplementary Figure 5. Schematic of FST CRISPR KO guides and in vivo experiment. A. Binding of the two commercially available FST CRISPR guides to FST to mediate KO. B. Mice were injected with SKOV3 cells expressing FST sgRNA #2. Mice were then treated 3 times with 10mg/kg Taxol intraperitoneal Paclitaxel at days 7, 14 and 21. C Dissection of control mice presenting with multiple metastases and an FST-KO mice which showed no residual disease. White arrows point to sites of disease.
Figure S1 from Quiescent Ovarian Cancer Cells Secrete Follistatin to Induce Chemotherapy Resistance in Surrounding Cells in Response to Chemotherapy
Authors: Cole Alexander J. , Panesso-Gómez Santiago , Shah Jaynish S. , Ebai Tonge , Jiang Qi , Gumusoglu-Acar Ece , Bello Maya G. , Vlad Anda , Modugno Francesmary , Edwards Robert P. , Buckanovich Ronald J.
Published: May 2023

Supplementary Figure 1. Histological analysis of PT340 cell line. PT340 cells were injected into NSG mice, and the resulting tumors were harvested for histological analysis, H&E staining showed features of Clear Cell Ovarian Carcinoma.
Supplementary Figure S7 from Durvalumab plus Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: An Open-label, Nonrandomized, Phase II Clinical Trial
Authors: Gulati Shuchi , Crist McKenzie , Riaz Muhammed Kashif , Takiar Vinita , Lehn Maria , Monroe Ilaina , Palackdharry Sarah , Kurtzweil Nicky , Jandarov Roman , Harun Nusrat , Wise-Draper Trisha M.
Published: May 2023

Supplementary Figures 7A, 7B and 7C Cetuximab enhances anti-tumor cytokines: Cytokine concentrations in the sample supernatants were determined by enzyme-linked immunosorbent assay (ELISA) using a Luminex assay (R&Dsystems, a bio-techne brand, Minneapolis, MN) according to the manufacturer's protocol. Cetuximab alone decreased pro-tumorigenic IL-6 levels and increased IP-10 suggesting an anti-tumor response (Supplementary Figure 7A and 7B); however, these cytokines were not significantly changed between responders (those with CR, PR, SD) and non-responders. The full panel of tested cytokines, shown in Supplementary Figure 7C.Abbreviations: CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; NK: Natural Killer; IL: interleukin; IP: Interferon gamma inducible protein-10 (IP-10).
Supplementary Figure S2 from Durvalumab plus Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: An Open-label, Nonrandomized, Phase II Clinical Trial
Authors: Gulati Shuchi , Crist McKenzie , Riaz Muhammed Kashif , Takiar Vinita , Lehn Maria , Monroe Ilaina , Palackdharry Sarah , Kurtzweil Nicky , Jandarov Roman , Harun Nusrat , Wise-Draper Trisha M.
Published: May 2023

Consort diagram of the clinical trial.Abbreviations: OS, overall survival; PFS, progression-free survival
Figure S4 from The Oncolytic Adenovirus XVir-N-31 Joins Forces with CDK4/6 Inhibition Augmenting Innate and Adaptive Antitumor Immunity in Ewing Sarcoma
Authors: Schober Sebastian Johannes , Schoening Caroline , Eck Jennifer , Middendorf Charlotte , Lutsch Julia , Knoch Pia , von Ofen Anna Josefine , Gassmann Hendrik , Thiede Melanie , Hauer Julia , Kolk Andreas , Mantwill Klaus , Gschwend Jürgen E. , Burdach Stefan E.G. , Nawroth Roman , Thiel Uwe , Holm Per Sonne
Published: May 2023

Supplemental Figure 4: Combination of XVir-N-31 and CDK4/6 inhibitor LEE011 induces an abscopal effect, induces monocyte infiltration and increases M1/M2 macrophage ratio in injected tumors.
Figure S3 from The Oncolytic Adenovirus XVir-N-31 Joins Forces with CDK4/6 Inhibition Augmenting Innate and Adaptive Antitumor Immunity in Ewing Sarcoma
Authors: Schober Sebastian Johannes , Schoening Caroline , Eck Jennifer , Middendorf Charlotte , Lutsch Julia , Knoch Pia , von Ofen Anna Josefine , Gassmann Hendrik , Thiede Melanie , Hauer Julia , Kolk Andreas , Mantwill Klaus , Gschwend Jürgen E. , Burdach Stefan E.G. , Nawroth Roman , Thiel Uwe , Holm Per Sonne
Published: May 2023

Supplemental Figure 3: Characterization of tumor-infiltrating T cells at the end of experiment (A673 xenografts).
Data from PSMA-positive Circulating Tumor Cell Detection and Outcomes with Abiraterone or Enzalutamide Treatment in Men with Metastatic Castrate-resistant Prostate Cancer
Authors: Gupta Santosh , Halabi Susan , Yang Qian , Roy Akash , Tubbs Alisa , Gore Yamini , George Daniel J. , Nanus David M. , Antonarakis Emmanuel S. , Danila Daniel C. , Szmulewitz Russell Z. , Wenstrup Richard , Armstrong Andrew J.
Published: May 2023

AbstractPurpose:
In men with metastatic castration-resistant prostate cancer (mCRPC), prostate-specific membrane antigen (PSMA)-targeted radioligand therapy has drastically improved clinical outcomes. A liquid biopsy characterizing PSMA expression could be useful in guiding optimal therapy.
Experimental Design:
We conducted a retrospective analysis of the prospective multicenter PROPHECY (Prospective CiRculating PrOstate Cancer Predictors in HighEr Risk mCRPC StudY) trial of men with mCRPC (n = 118) treated with abiraterone (abi) or enzalutamide (enza). Circulating tumor cells (CTC) were enriched (CTC/mL) and characterized for PSMA protein expression/heterogeneity at baseline and progression. We utilized proportional hazards modeling of the association between PSMA-positive (PSMA+) CTC enumeration with overall survival (OS) and progression-free survival (PFS).
Results:
Overall, 97 men with mCRPC had evaluable blood samples for baseline CTC PSMA detection; 78 men (80%) had detectable CTCs. Of these, 55% (43/78) of men had any PSMA CTC detection, 21% (16/78) had ≥2 PSMA+ CTCs/mL, and 19% (8/43) were 100% PSMA+. At progression on abi/enza, 88% (50/57) of men had detectable CTCs, 68% (34/50) had any PSMA CTCs, and 12% (4/34) had 100% PSMA+ CTCs. Among paired cases (n = 57), PSMA+ CTC detection increased slightly after abi/enza progression. Using an optimal cutoff of ≥2 PSMA+ CTCs/mL, median OS was 26, 21, and 11 months for men without CTCs, PSMA− CTCs, and PSMA+ CTCs. Adjusting for prior abi/enza therapy, Halabi clinical risk score, and CTC enumeration, the HRs for OS and PFS for PSMA+ CTC+ were 3.0 [95% confidence interval (CI) = 1.1–7.8] and 2.3 (95% CI = 0.9–5.8).
Conclusions:
We observed PSMA CTC heterogeneity between and within patients with mCRPC over time during abi/enza progression. CTC PSMA enumeration was adversely prognostic independent of clinical factors and disease burden. Further validation is warranted in the context of PSMA-targeted therapies.
Data 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: May 2023

AbstractPurpose:
Inhibitors of Bruton's tyrosine kinase (BTKi) and PI3K (PI3Ki) have significantly improved therapy of chronic lymphocytic leukemia (CLL). However, the emergence of resistance to BTKi has introduced an unmet therapeutic need. Hence, we sought evidence for essential roles of PI3K-δi and PI3K-γi in treatment-naïve and BTKi-refractory CLL.
Experimental Design:
Responses to PI3K-δi, PI3K-γi, and the dual-inhibitor duvelisib in each B, T, and myeloid cell compartments of CLL were studied in vitro, and in a xenograft mouse model using primary cells from treatment-naïve and ibrutinib-resistant patients, and finally, in a patient with ibrutinib-resistant CLL treated with duvelisib.
Results:
We demonstrate the essential roles of PI3K-δ for CLL B-cell survival and migration, of PI3K-γ for T-cell migration and macrophage polarization, and of dual inhibition of PI3K-δ,γ for efficacious reduction of leukemia burden. We also show that samples from patients whose disease progressed on ibrutinib were responsive to duvelisib therapy in a xenograft model, irrespective of BTK mutations. In support of this, we report a patient with ibrutinib-resistant CLL, bearing a clone with BTK and PLCγ2 mutations, who responded immediately to single-agent duvelisib with redistribution lymphocytosis followed by a partial clinical remission associated with modulation of T and myeloid cells.
Conclusions:
Our data define the mechanism of action whereby dual inhibition of PI3K-δ,γ affects CLL B-cell numbers and T and myeloid cell pro-leukemia functions and support the use of duvelisib as a valuable approach for therapeutic interventions, including for patients refractory to BTKi.
Multicenter Randomized Double-Blind Phase III Trial of Donafenib in Progressive Radioactive Iodine-Refractory Differentiated Thyroid Cancer
Authors: Lin Yansong , Qin Shukui , Yang Hui , Shi Feng , Yang Aimin , Han Xingmin , Liu Bin , Li Zhiyong , Ji Qinghai , Tang Lijun , Deng Zhiyong , Ding Yong , Fu Wei , Xie Xianhe , Li Linfa , He Xiaohui , Lv Zhongwei , Ma Qingjie , Shen Zan , Guo Zhuming , Chen Zhendong , Cui Yali , Tan Jian , Gao Zairong , Jing Shanghua , Lu Keyi , Luo Xianyang , Zhang Yuan , Fang Yong , Li Zhendong , Cheng Yizhuang , Lei Shangtong , Luan Sha , Chen Guang , Wang Guihua , Wu Liqing , Liu Lingling
Published: May 2023

Purpose:

The phase II/III study of donafenib was initiated when there was no available treatment indicated for Chinese patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC). Donafenib, an oral tyrosine kinase inhibitor (TKI), showed good efficacy and tolerability in the phase II study. We aimed to further evaluate the antitumor activity and safety of donafenib in Chinese patients with RAIR-DTC.

Patients and Methods:

This multicenter, double-blind, placebo-controlled, phase III study enrolled 191 patients with progressive RAIR–DTC and randomized in a ratio of 2:1 to donafenib (300 mg twice daily, n = 128) or matched placebo (n = 63). An open-label donafenib treatment period was allowed upon disease progression. The primary endpoint was progression-free survival (PFS) assessed by the independent review committee. The second endpoints include objective response rate (ORR), disease control rate (DCR), safety, etc.

Results:

Donafenib demonstrated prolonged median PFS over placebo [12.9 vs. 6.4 months; hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.25–0.61; P < 0.0001] in Chinese patients with RAIR–DTC. Improved ORR (23.3% vs. 1.7%; P = 0.0002) and DCR (93.3% vs. 79.3%; P = 0.0044) were observed in the donafenib group over placebo. For donafenib, the most common grade ≥ 3 treatment-related adverse events (AE) included hypertension (13.3%) and hand–foot syndrome (12.5%), 42.2% underwent dose reduction or interruption, and 6.3% experienced discontinuation.

Conclusions:

Donafenib was well-tolerated and demonstrated clinical benefit in terms of improved PFS, ORR, and DCR in patients with RAIR-DTC. The results suggest that donafenib could be a new treatment option for patients with RAIR-DTC.
Table S1 from Development of an Anti-canine PD-L1 Antibody and Caninized PD-L1 Mouse Model as Translational Research Tools for the Study of Immunotherapy in Humans
Authors: Oh Wonkyung , Kim Alyssa Min Jung , Dhawan Deepika , Kirkham Perry M. , Ostafe Raluca , Franco Jackeline , Aryal Uma K. , Carnahan Robert H. , Patsekin Valery , Robinson J. Paul , Knapp Deborah W. , Lim Seung-Oe
Published: May 2023

The list of genes that were altered in the activated canine PBMCs from the nCounter canine immune-oncology panel analysis
Data from Development of an Anti-canine PD-L1 Antibody and Caninized PD-L1 Mouse Model as Translational Research Tools for the Study of Immunotherapy in Humans
Authors: Oh Wonkyung , Kim Alyssa Min Jung , Dhawan Deepika , Kirkham Perry M. , Ostafe Raluca , Franco Jackeline , Aryal Uma K. , Carnahan Robert H. , Patsekin Valery , Robinson J. Paul , Knapp Deborah W. , Lim Seung-Oe
Published: May 2023

Immune checkpoint blockade therapy, one of the most promising cancer immunotherapies, has shown remarkable clinical impact in multiple cancer types. Despite the recent success of immune checkpoint blockade therapy, however, the response rates in patients with cancer are limited (∼20%–40%). To improve the success of immune checkpoint blockade therapy, relevant preclinical animal models are essential for the development and testing of multiple combination approaches and strategies. Companion dogs naturally develop several types of cancer that in many respects resemble clinical cancer in human patients. Therefore, the canine studies of immuno-oncology drugs can generate knowledge that informs and prioritizes new immuno-oncology therapy in humans. The challenge has been, however, that immunotherapeutic antibodies targeting canine immune checkpoint molecules such as canine PD-L1 (cPD-L1) have not been commercially available. Here, we developed a new cPD-L1 antibody as an immuno-oncology drug and characterized its functional and biological properties in multiple assays. We also evaluated the therapeutic efficacy of cPD-L1 antibodies in our unique caninized PD-L1 mice. Together, these in vitro and in vivo data, which include an initial safety profile in laboratory dogs, support development of this cPD-L1 antibody as an immune checkpoint inhibitor for studies in dogs with naturally occurring cancer for translational research. Our new therapeutic antibody and caninized PD-L1 mouse model will be essential translational research tools in raising the success rate of immunotherapy in both dogs and humans.
Significance:
Our cPD-L1 antibody and unique caninized mouse model will be critical research tools to improve the efficacy of immune checkpoint blockade therapy in both dogs and humans. Furthermore, these tools will open new perspectives for immunotherapy applications in cancer as well as other autoimmune diseases that could benefit a diverse and broader patient population.
Modeling Rice Production in West Java by Means Geographically Weighted Regression
Authors: Sobari Muhamad , Jaya I Gede Nyoman Mindra
Published: May 2023

In Indonesia, rice production varies from province to province, resulting in both large and small disparities between provinces. In Indonesia, East Java, Central Java and West Java Provinces have the highest rice production. In contrast to East Java and Central Java, however, the total rice consumption per year in West Java is the highest. In linear regression, the coefficients are the same for all regions, while each region sometimes has different influencing factors, resulting in spatial diversity. Consequently, the Geographically Weighted Regression (GWR) method was used to model the rice production of West Java Provincial regencies/municipalities by accounting for spatial heterogeneity. The GWR model employs the fixed bi-square kernel function as its weighting function. This model includes five explanatory variables, such as number of agricultural labor, number of used rice seed, number of two-wheel tractor, number of water pump, and number of farmer groups, with rice production as the response variable. GWR model has greater coefficient determination (96.8 percent) and smaller AIC values (920.76) than global regression. During the period of 2018-2020, the number of two-wheel tractors and the number of water pumps had the greatest impact on rice production in West Java and the number of two-wheeled tractors and the number of farmer groups variables has an effect on rice production in most regencies/municipalities in West Java. There are 11 groups of areas which has the similarity of significant predictor variables.
Pengaruh Analisis Kebangkrutan Model Altman Z-score Terhadap Harga Saham Pada Perusahaan Manufaktur di Bursa Efek Indonesia Sebelum dan Saat Pandemi Covid -19
Authors: Suryana Ade , Anggraeny Ayu Dila
Published: May 2023

Penelitian ini bertujuan untuk mengetahui pengaruh pengaruh Altman Z-Score terhadap harga saham, pengaruh rasio-rasio pada Altman Z-score terhadap harga saham sebelum dan saat pandemi covid-19, dan mengetahui perbedaan rasio-rasio pada Altman Z- score sebelum dan saat pandemic covid-19 pada perusahaan manufaktur yang terdaftar dalam Bursa Efek Indonesia (BEI) periode 2019-2020. Jenis penelitian ini menggunakan pendekatan kuantitatif dengan metode Purposive Sampling. Terdapat 14 Sampel Perusahaan yang sesuai dengan kriteria yang ditentukan. Hasil penelitian ini menunjukkan bahwa pada regresi linier sederhana nilai Altman Z-score tidak berpengaruh terhadap harga saham sebelum pandemi covid-19 dan saat pandemi covid -19.
Determinan Produk Domestik Bruto di Provinsi Bali Tahun 2014-2019
Authors: Wahyuni Desak Ari Gita , Muchtar Masruri , Sihombing Pardomuan Robinson
Published: May 2023

This study aims to analyze the components of the Human Development Index on Gross Regional Domestic Product (GRDP) in Bali during the 2014-2019 period. The data used are time series and cross section obtained and processed from the Central Bureau of Statistics. Through a quantitative descriptive approach, this study uses multiple linear regression methods on panel data with the selected estimation model being the Fixed Effect Model. The results showed that the dependent variable of GRDP could be explained by independent variables by 92.03 percent and 7.97 percent of it was influenced by other variables outside this research model. Mean Years School and Life Expectancy variable have a positive effect on GRDP while the Labor Force Participation Rate variable has a negative and insignificant effect on GRDP. Government policies are needed to support equitable distribution of human development in each region
Magnetic Resonance Imaging and Computed Tomography for the Noninvasive Assessment of Arterial Aging: A Review by the VascAgeNet COST Action
Authors: Bianchini Elisabetta , Lønnebakken Mai Tone , Wohlfahrt Peter , Piskin Senol , Terentes‐Printzios Dimitrios , Alastruey Jordi , Guala Andrea
Published: May 2023

Magnetic resonance imaging and computed tomography allow the characterization of arterial state and function with high confidence and thus play a key role in the understanding of arterial aging and its translation into the clinic. Decades of research into the development of innovative imaging sequences and image analysis techniques have led to the identification of a large number of potential biomarkers, some bringing improvement in basic science, others in clinical practice. Nonetheless, the complexity of some of these biomarkers and the image analysis techniques required for their computation hamper their widespread use. In this narrative review, current biomarkers related to aging of the aorta, their founding principles, the sequence, and postprocessing required, and their predictive values for cardiovascular events are summarized. For each biomarker a summary of reference values and reproducibility studies and limitations is provided. The present review, developed in the COST Action VascAgeNet, aims to guide clinicians and technical researchers in the critical understanding of the possibilities offered by these advanced imaging modalities for studying the state and function of the aorta, and their possible clinically relevant relationships with aging.
Risk Factor Interactions, Non–High‐Density Lipoprotein Cholesterol to Apolipoprotein B Ratio, and Severity of Coronary Arteriosclerosis in South Asian Individuals: An Observational Cohort Study
Authors: Molina César R. , Mathur Ashish , Soykan Candan , Sathe Anita , Kunhiraman Leela
Published: May 2023

Background

South Asian individuals are at higher risk for arteriosclerotic cardiovascular disease and diabetes. The factors associated with arteriosclerotic cardiovascular disease severity and their interactions are unknown.

Methods and Results

This is a retrospective cohort study of the first 1162 South Asian participants enrolled in the South Asian Heart Center's AIM to Prevent Program who completed noncontrast coronary computed tomography scans. Using machine‐learning algorithms, we identified and modeled the interaction of predictor variables with coronary artery calcification (CAC) severity in South Asian individuals. Anthropometric, laboratory, demographic, and lifestyle predictor variables were analyzed using continuous boosted regression trees to model the relationship with and in between predictor variables and CAC. Participants with CAC were older, predominately men, had smoking history, had personal histories of diabetes, hypertension, and hypercholesterolemia, and had family histories of coronary artery disease. Insulin, body mass index, blood pressure, fasting blood sugar, hemoglobin A1c, and waist‐to‐height ratio were associated with CAC but not low‐density lipoprotein cholesterol or lipoprotein (a). The arteriosclerotic cardiovascular disease score failed to classify individuals. Only age, body mass index, non–high‐density lipoprotein cholesterol/apolipoprotein B ratio, smoking risk, fasting blood sugar, and diastolic blood pressure were predictive, explaining 30.3% of CAC severity. A non–high‐density lipoprotein cholesterol/apolipoprotein B ratio of 1.4 or less markedly increased coronary calcification.

Conclusions

Our findings highlight factors associated with dysmetabolism and cholesterol‐depleted non–high‐density lipoprotein cholesterol particles with coronary arteriosclerosis, possibly explaining the dual epidemics of diabetes and arteriosclerotic cardiovascular disease in this population. Markers of glucose dysmetabolism and the non–high‐density lipoprotein cholesterol to apolipoprotein B ratio should become the focus of assessment for cardiovascular risk in South Asian individuals, with prevention strategies directed at improving glucose metabolic health.
Identification of Optical Coherence Tomography‐Defined Coronary Plaque Erosion by Preprocedural Computed Tomography Angiography
Authors: Nagamine Tatsuhiro , Hoshino Masahiro , Yonetsu Taishi , Sugiyama Tomoyo , Kanaji Yoshihisa , Matsuda Kazuki , Sayama Kodai , Ueno Hiroki , Nogami Kai , Hanyu Yoshihiro , Misawa Toru , Hada Masahiro , Usui Eisuke , Sasano Tetsuo , Kakuta Tsunekazu
Published: May 2023

Background

A previous coronary computed tomography (CT) angiographic study failed to discriminate optical coherence tomography‐defined intact fibrous cap culprit lesions (IFC group) from those with ruptured fibrous caps (RFC group) in patients with coronary artery disease. This study aimed to evaluate the diagnostic efficacy of preprocedural coronary CT imaging in identifying subsequently performed optical coherence tomography‐defined plaque rupture or erosion at culprit lesions in patients with non–ST‐segment–elevation acute myocardial infarction.

Methods and Results

This study used data from 2 recently published studies that tested the hypothesis that coronary CT angiography (CCTA) before percutaneous coronary intervention may provide diagnostic information on the high‐risk atherosclerotic burden in patients with non–ST‐segment–elevation acute myocardial infarction. In the analysis of 186 patients, optical coherence tomography identified 106 RFC plaques and 80 IFC plaques as the culprit lesions. On CT, the prevalence of low‐attenuation plaque, positive remodeling, napkin‐ring sign, and spotty calcification were all significantly lower in the IFC group. The culprit vessel pericoronary adipose tissue inflammation and coronary artery calcium scores were significantly lower in the IFC group than in the RFC group. The absence of low‐attenuation plaque, napkin‐ring sign, zero coronary artery calcium, and low pericoronary adipose tissue inflammation were independent predictors of IFC. When stratified into 5 subgroups according to the number of these 4 CT factors, the prevalence of IFC was 8.3%, 20.8%, 44.6%, 75.6%, and 100% (
P
<0.001), respectively.

Conclusions

Preprocedural comprehensive coronary CT imaging, including coronary artery calcium and pericoronary adipose tissue inflammation assessment, can accurately and noninvasively identify optical coherence tomography‐defined IFC or RFC culprit lesions.
Does the dGEMRIC Index Recover 3 Years After Surgical FAI Correction and an Initial dGEMRIC Decrease at 1-Year Follow-up? A Controlled Prospective Study
Authors: Meier Malin Kristin , Scheuber Samira , Hanke Markus Simon , Haefeli Pascal Cyrill , Ruckli Adrian Cyrill , Liechti Emanuel Francis , Gerber Nicolas , Lerch Till Dominic , Tannast Moritz , Siebenrock Klaus Arno , Steppacher Simon Damian , Schmaranzer Florian
Published: May 2023

Background:

Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) allows objective and noninvasive assessment of cartilage quality. An interim analysis 1 year after correction of femoroacetabular impingement (FAI) previously showed that the dGEMRIC index decreased despite good clinical outcome.

Purpose:

To evaluate dGEMRIC indices longitudinally in patients who underwent FAI correction and in a control group undergoing nonoperative treatment for FAI.

Study Design:

Cohort study; Level of evidence, 3.

Methods:

This prospective, comparative longitudinal study included 39 patients (40 hips) who received either operative (n = 20 hips) or nonoperative (n = 20 hips) treatment. Baseline demographic characteristics and presence of osseous deformities did not differ between groups. All patients received indirect magnetic resonance arthrography at 3 time points (baseline, 1 and 3 years of follow-up). The 3-dimensional cartilage models were created using a custom-developed deep learning–based software. The dGEMRIC indices were determined separately for acetabular and femoral cartilage. A mixed-effects model was used for statistical analysis in repeated measures.

Results:

The operative group showed an initial (preoperative to 1-year follow-up) decrease of dGEMRIC indices: acetabular from 512 ± 174 to 392 ± 123 ms and femoral from 530 ± 173 to 411 ± 117 ms (both P < .001). From 1-year to 3-year follow-up, dGEMRIC indices improved again: acetabular from 392 ± 123 to 456 ± 163 ms and femoral from 411 ± 117 to 477 ± 169 ms (both P < .001). The nonoperative group showed no significant changes in dGEMRIC indices in acetabular and femoral cartilage from baseline to either follow-up point (all P > .05).

Conclusion:

This study showed that 3 years after FAI correction, the dGEMRIC indices improved compared with short-term 1-year follow-up. This may be due to normalized joint biomechanics or regressive postoperative activation of the inflammatory cascade after intra-articular surgery.