bluuebunny/crossref_metadata_2025 huggingface dataset:
A Nomogram for Predicting Physical Restraint of Patients in Intensive Care Unit
Authors: Wang Yun , Liu Ying , Tian Ya-Li , Gu Su-Lian
Published: April 2023

Background. Despite its ethical implications, physical restraint (PR) is widely used in the intensive care unit (ICU) to guarantee the safety of patients. This study investigated the frequency and risk factors of PR use for patients in the ICU to establish a predictive nomogram. Methods. Clinical parameters of patients admitted to the ICU of Jiangsu Province Hospital from January 2021 to July 2021 were retrospectively collected. Independent risk factors of PR were analyzed by univariate and multivariate logistic regression analyses. The R software was used to establish the nomogram. Model performance was validated using the concordance-index (C-index) and calibration curves. Results. The rate of PR use was 46.32% (233/503 patients). Age (B = 0.036, odds ratio [OR]: 1.037, 95% confidence interval [CI]: 1.022–1.052,

P
<
0.001

), consciousness disorder (B = 0.770, OR: 2.159, 95% CI: 1.216–3.832,

P
=
0.009

), coma (B = −1.666, OR: 0.189, 95% CI: 0.101–0.353,

P
<
0.001

), passive activity (B = 1.014, OR: 2.756, 95% CI: 1.644–4.618,

P
<
0.001

), delirium (B = 0.993, OR: 2.699, 95% CI: 1.097–6.642,

P
=
0.031

), −3 < Richmond Agitation Sedation Scale (RASS) score <2 (B = 0.698, OR: 2.009, 95% CI: 1.026–3.935,

P
=
0.042

), RASS score ≥2 (B = 1.253, OR: 3.499, 95% CI: 1.126–10.875,

P
=
0.030

), and mechanical ventilation (B = 1.696, OR: 5.455, 95% CI: 2.804–10.611,

P
<
0.001

) were identified as independent risk factors for PR in the ICU (

P
<
0.05

) and included in the nomogram. The C-index was 0.830, and the calibration curve indicated good discriminatory ability and accuracy (mean absolute error: 0.026). Conclusion. The prediction nomogram model of PR in ICU was established based on age, mobility, delirium, consciousness, RASS score, and mechanical ventilation. It showed good discrimination and accuracy. This nomogram may predict the probability of PR use in the ICU and guide nurses in developing precise interventions to reduce the rate of PR.
Inhibition of TRF2 Leads to Ferroptosis, Autophagic Death, and Apoptosis by Causing Telomere Dysfunction
Authors: Yang Qiuhui , Nie Ziyang , Zhu Yukun , Hao Mingying , Liu Siqi , Ding Xuelu , Wang Feng , Wang Fei , Geng Xin
Published: April 2023

Background. Gastric cancer (GC) is an aggressive malignancy with a high mortality rate and poor prognosis. Telomeric repeat-binding factor 2 (TRF2) is a critical telomere protection protein. Emerging evidence indicates that TRF2 may be an essential treatment option for GC; however, the exact mechanism remains largely unknown. Objective. We aimed to explore the role of TRF2 in GC cells. The function and molecular mechanisms of TRF2 in the pathogenesis of GC were mainly discussed in this study. Methods. Relevant data from GEPIA and TCGA databases regarding TRF2 gene expression and its prognostic significance in GC samples were analyzed. Analysis of 53BP1 foci at telomeres by immunofluorescence, metaphase spreads, and telomere-specific FISH analysis was carried out to explore telomere damage and dysfunction after TRF2 depletion. CCK8 cell proliferation, trypan blue staining, and colony formation assay were performed to evaluate cell survival. Apoptosis and cell migration were determined with flow cytometry and scratch-wound healing assay, respectively. qRT-PCR and Western blotting were carried out to analyze the mRNA and protein expression levels after TRF2 depletion on apoptosis, autophagic death, and ferroptosis. Results. By searching with GEPIA and TCGA databases, the results showed that the expression levels of TRF2 were obviously elevated in the samples of GC patients, which was associated with adverse prognosis. Knockdown of TRF2 suppressed the cell growth, proliferation, and migration in GC cells, causing significant telomere dysfunction. Apoptosis, autophagic death, and ferroptosis were also triggered in this process. The pretreatment of chloroquine (autophagy inhibitor) and ferrostatin-1 (ferroptosis inhibitor) improved the survival phenotypes of GC cells. Conclusion. Our data suggest that TRF2 depletion can inhibit cell growth, proliferation, and migration through the combined action of ferroptosis, autophagic death, and apoptosis in GC cells. The results indicate that TRF2 might be used as a potential target to develop therapeutic strategies for treating GC.
Oil Spill Cleanup Employing Surface Modified Magnetite Nanoparticles Using Two New Polyamines
Authors: Abdullah Mahmood M. S. , Ali Mohd Sajid , Al-Lohedan Hamad A.
Published: April 2023

Oil spills in marine environments are a serious environmental concern and using low-cost materials for oil spill cleanup is an emerging subject. In recent years, surface-modified magnetite nanoparticles (MNPs) have shown promising properties for oil spill cleanup due to their high performance, low cost, magnetic properties, and reusability. This study aims to modify the surface of magnetite nanoparticles (MNPs) using two new polyamines and employ them for oil spill remediation. First, tetraethylene glycol (TEG) was converted to the corresponding alkyl halide (AH). Next, two polyamines were synthesized via the alkylation of diamines, 1,11-undecanediamine (UD) and 1,5-pentanediamine (PD), yielding the corresponding AH-UD and AH-PD polyamines. Finally, AH-UD and AH-PD were applied to MNPs’ surface modification, yielding the corresponding surface-modified MNPs, AU-MNPs, and AP-MNPs. The performance of AU-MNPs and AP-MNPs for oil spill uptake (OSU%) was investigated using various MNPs-to-oil ratios at different contact times. Furthermore, the reusability of AU-MNPs and AP-MNPs was also investigated over four cycles. The results indicated that the OSU values of AU-MNPs and AP-MNPs were affected by MNPs’ ratios and contact time, where their OSU increased as their ratios and contact time increased. In addition, AU-MNPs showed a higher OSU than AP-MNPs, which could be ascribed to the longer alkyl chain in the polyamine (AH-UA) used for their surface modification compared to AP-MNPs. Furthermore, AU-MNPs and AP-MNPs reusability results exhibited effective OSU in four cycles with a relative decline with an increasing number of cycles.
Management of Lobular Neoplasia Diagnosed by Core Biopsy
Authors: Jani Chinmay , Lotz Margaret , Keates Sarah , Gupta Yasha , Walker Alexander , Al Omari Omar , Parvez Arshi , Patel Dipesh , Gnata Maria , Perry John , Khorashadi Leila , Weissmann Lisa , Pories Susan E.
Published: April 2023

Lobular neoplasia (LN) involves proliferative changes within the breast lobules. LN is divided into lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH). LCIS can be further subdivided into three subtypes: classic LCIS, pleomorphic LCIS, and LCIS with necrosis (florid type). Because classic LCIS is now considered as a benign etiology, current guidelines recommend close follow-up with imaging versus surgical excision. The goal of our study was to determine if the diagnosis of classic LN on core needle biopsy (CNB) merits surgical excision. This is a retrospective, observational study conducted at Mount Auburn Hospital, Cambridge, MA, from May 17, 2017, through June 30, 2020. We reviewed the data of breast biopsies conducted at our hospital over this period and included patients who were diagnosed with classic LN (LCIS and/or ALH) and excluded patients having any other atypical lesions on CNB. All known cancer patients were excluded. Of the 2707 CNBs performed during the study period, we identified 68 women who were diagnosed with ALH or LCIS on CNB. CNB was performed for an abnormal mammogram in the majority of patients (60; 88%) while 7(10.3%) had an abnormal breast magnetic resonance imaging study (MRI), and 1 had an abnormal ultrasound (US). A total of 58 patients (85%) underwent excisional biopsy, of which 3 (5.2%) showed malignancy, including 2 cases of DCIS and 1 invasive carcinoma. In addition, there was 1 case (1.7%) with pleomorphic LCIS and 11 cases with ADH (15.5%). The management of LN found on core biopsy is evolving, with some advocating surgical excision and others recommending observation. Our data show a change in diagnosis with excisional biopsy in 13 (22.4%) of patients with 2 cases of DCIS, 1 invasive carcinoma, 1 pleomorphic LCIS, and 9 cases of ADH, diagnosed on excisional biopsy. While ALH and classic LCIS are considered benign, the choice of ongoing surveillance versus excisional biopsy should be made with shared decision making with the patient, with consideration of personal and family history, as well as patient preferences.
Artificial Intelligence-Based Digital Media Design Effect Enhancement Mechanism
Authors: Zhao Pu
Published: April 2023

The advancement of AI technology has promoted the development speed of digital multimedia and brought a new experience to the digital media experience effect. In this paper, we aim to using artificial intelligence methods to enhance the digital media design experience. Specifically, we propose a method for low-light image enhancement using generative adversarial networks as a model framework. To better solve the problem, we design the following strategies in our proposed method. First, we preprocess the images into patches with a proper size. Second, we introduce the overall network structure of GAN. Third, we designed a multifeature extraction module with different sizes of convolution kernels to enhance the model’s ability for extracting features. Fourth, we propose a loss that combines the mean square error distance function with the adversarial error function to enable the model to learn the distributional features of the image. Finally, we verify the effectiveness of the proposed method on two datasets, namely, PASCAL VOC and MIT-Adobe FiveK. The results show that our proposed method performs well in the process of evaluation.
Optimization Process of Potassium Carbonate Activated Carbon through Jute-Based Core Materials by Using Artificial Neural Network with Response Surface Methodology
Authors: Natrayan L. , Niveditha V. R. , Kaliappan S. , Patil Pravin P. , Pandian C. K. Arvinda , Rao Y. Sesha , Murugan P.
Published: April 2023

Potassium carbonate was tested as novel information for producing carbonaceous materials from jute cores. Two quadratic models have been developed for both answers to link the preparatory parameters: activating temperatures, molar ratio, and incubation time. The RSM and ANN models were used to improve the processing conditions to maximise the quantities of iodine and methylene blue penetration. The best charcoal was obtained using 900°C activating temperatures, a 1.5 molar ratio, and a 4-hour activating time. This resulted in iodine and methylene blue absorption of 1260.07 mg/g and 369.21 mg/g, respectively. It was discovered that the K2CO3-based pyrolysis process might be anticipated to become a safe yet incredibly efficient process of making activated carbons with a very well-defined and monocultural porous structure. Even though the precise emphasis given to K2CO3 is unknown at the moment, given the creation of K2C3O4 just after evolvement with one additional molarity of CO at approximately 870°C, these same porous and papule responses begun by K2CO3 stimulation might be temporarily posited to be quite comparable to an initiation action needed to make progress by K2C3O4. The influence of control parameters was examined in this study using variance analysis like the ANOVA test. Furthermore, the response surface (RSM) and artificial neural networks (ANN) are employed to improve the output results while optimising the methylene blue and iodine qualities. Consequently, the experimental findings correlate well with the statistics.
The Impact of Classical Cardiovascular Risk Factors on Hospitalization and Mortality among Hajj Pilgrims
Authors: Ardiana Meity , Utami Eka Rahayu , Al Farabi Makhyan Jibril , Azmi Yusuf
Published: April 2023

Background. Cardiovascular disease (CVD) is the leading cause of morbidity and mortality during Hajj. The objective of the present study was to examine the effect of classical cardiovascular disease risk factors on mortality and hospitalization among Hajj pilgrims from East Java, Indonesia, during 2017, 2018, and 2019. Methods. This study was a retrospective cohort of Hajj pilgrims from East Java, Indonesia, from 2017 to 2019. The data on risk factors were obtained from the pre-embarkation Hajj screening records. The diagnosis of hospitalization and cause of death during the Hajj period were obtained from the medical report and hospital/flight doctor death certificate. Results. A total of 72078 eligible subjects were included in this study. 33807 (46.9%) were men, and 38271 (53.1%) were women, and the majority (35%) were aged between 50 and 59 years. A total of 42446 pilgrims (58.9%) were classified as high risk due to underlying health conditions such as hypertension, diabetes, or if they were aged 60 years or older. The overall hospitalization rate is 971 per 100,000 pilgrims and the overall death rate is 240 deaths per 100,000 pilgrims. Multivariate analysis using logistic regression showed that male gender, age > 50 years, hypertension grade II-III, diabetes, overweight, and obesity were associated with a higher risk of hospitalization. Moreover, male gender, diabetes, and overweight were associated with a higher risk of mortality. Of all hospitalized patients, 92 patients (13.1%) had an initial diagnosis of CVD, and CVD is the main cause of mortality (38.2%) of pilgrims. Conclusion. Pilgrims with classical cardiovascular risk factors were associated with increased hospitalization and mortality.
Progressive Failure of Surrounding Rock in Underground Engineering and Size Effect of Numerical Simulation
Authors: Zhong Daning , Chen Jianlin , Zhou Hui , Chen Xiangrong , Jiang Yali
Published: April 2023

The analysis and simulation of progressive failure of surrounding rock is very important for analyzing the stability of surrounding rock in underground engineering. Size effect is also a key problem worth further study in engineering. Taking the underground powerhouse on the right bank of Baihetan as an example, the acoustic test results are collected and the relaxation and failure characteristics of the surrounding rock are summarized. Then, the numerical simulation of progressive failure of surrounding rock of underground powerhouse is carried out by using the finite discrete element method CDEM (continuum-based discrete element method). The results are compared with the acoustic test results of the surrounding rock relaxation layer, and the stress and displacement of surrounding rock characteristic points are analyzed. At the same time, the size effect of grid and mechanical parameter in the process of numerical simulation are discussed. The calculated fracture depth of surrounding rock is in good agreement with the acoustic test results, which shows the reliability of progressive failure simulation of surrounding rock of the underground powerhouse. When CDEM is used to simulate the excavation of tunnels with different tunnel diameters, the minimum grid size should be about 1% of the tunnel diameter. The mechanical parameters of rock mass have significant size effect, which needs to be analyzed in detail. The research results prove the superiority of the CDEM method in simulating the progressive failure of hard surrounding rock and its unique size effect characteristics, which can provide technical reference for the application of the CDEM method in other similar engineering problems.
Boundedness of
p
-Adic Singular Integrals and Multilinear Commutator on Morrey-Herz Spaces
Authors: Shi Yanlong , Li Li , Shen Zhonghua
Published: April 2023

In this paper, we establish the boundedness of classical

p

-adic singular integrals on Morrey-Herz spaces, as well as the boundedness of multilinear commutator generated by

p

-adic singular integral operators and Lipschitz functions or by

p

-adic singular integral operators and

λ

-central BMO functions.
Effect of Production Factors on the Bioethanol Yield of Tropical Sawdust
Authors: Amaefule Desmond , Nwakaire Joel , Ogbuagu Nneka , Anyadike Chinenye , Ogenyi Chiamaka , Ohagwu Chukwuemeka , Egbuhuzor Onyekachi
Published: April 2023

Bioethanol production from cellulosic materials is important in mitigating the concomitant displacement and exploitation of primary food crops for biofuel production and reducing carbon emissions which exacerbate climate change. The problem of reduced yield in the production and availability of yeast locally poses a barrier to market adoption and penetration of bioethanol. The study examined the effect of particle size and different yeast strains on the yield of bioethanol from waste sawdust that was sourced from a local timber processing centre. The samples of yeast were prepared from baker’s yeast (Saccharomyces cerevisiae) and palm wine yeast (Saccharomyces chevalieri). The sawdust was reduced to 212 μm, 300 μm, and 500 μm particle sizes. The samples of each particle size were pretreated and hydrolyzed with H2SO4 and fermented with S. cerevisiae or S. chevalieri yeast. The results obtained show that the weight, pH, density, viscosity, flash point, and heating value of the produced bioethanol ranged between 221.67 and 322.64 g, 6.2 and 6.6, 0.821 and 0.878 g/mL, 1.073 and 1.193, 14 and 16°C, and 20.5 and 23.1 MJ/kg, respectively, while the alcohol content of each of the samples was 69%. Furthermore, the bioethanol yield from Saccharomyces cerevisiae yeast was 213.9 mL, 193.2 mL, and 186.3 mL, for the 212 μm, 300 μm, and 500 μm particles, while for Saccharomyces chevalieri yeast, the yield was 289.8 mL, 255.3 mL, and 220.8 mL for the 212 μm, 300 μm, and 500 μm, respectively. An ANOVA on the effect of particle size on ethanol yield shows a significant difference at 5% level of significance. The study demonstrated that the use of locally produced yeast and increasing the surface area of sawdust increase bioethanol yield. Hence, it was concluded that better yeast strain use and biomass particle size reduction to a level that allows the optimal surface area for the reaction improve the yield of bioethanol. The study outcome can help in ameliorating the continued dependence on fossil fuels and the food security problems arising from displacing or utilizing food for fuel and could also encourage commercial-scale cellulosic ethanol production from waste.
Supplementary Table 1 from Prevalence and Prognostic Significance of Malnutrition in Patients with Brain Metastasis
Authors: Liu Zheran , Zhang Yu , Pei Yiyan , He Yan , Yu Jiayi , Zhang Renjie , Wang Jingjing , Chong Weelic , Hai Yang , Peng Xingchen , Fang Fang
Published: April 2023

Supplementary Table 1. The comparison of baseline characteristics of included and excluded patients with brain metastases.
Supplementary Figure 4 from Prevalence and Prognostic Significance of Malnutrition in Patients with Brain Metastasis
Authors: Liu Zheran , Zhang Yu , Pei Yiyan , He Yan , Yu Jiayi , Zhang Renjie , Wang Jingjing , Chong Weelic , Hai Yang , Peng Xingchen , Fang Fang
Published: April 2023

Supplementary Figure 4 The Sankey plot showing the relationship between different malnutrition categories.
Risk Factors and Trends for HPV-Associated Subsequent Malignant Neoplasms among Adolescent and Young Adult Cancer Survivors
Authors: Ou Judy Y. , Bennion Natalie , Parker Kellee , Fair Douglas , Hanson Heidi A. , Kepka Deanna , Warner Echo L. , Ramsay Joemy M. , Kaddas Heydon K. , Kirchhoff Anne C.
Published: April 2023

Background:

Subsequent malignant neoplasms (SMN; new cancers that arise after an original diagnosis) contribute to premature mortality among adolescent and young adult (AYA) cancer survivors. Because of the high population prevalence of human papillomavirus (HPV) infection, we identify demographic and clinical risk factors for HPV-associated SMNs (HPV-SMN) among AYA cancer survivors in the SEER-9 registries diagnosed from 1976 to 2015.

Methods:

Outcomes included any HPV-SMN, oropharyngeal-SMN, and cervical-SMN. Follow-up started 2 months after their original diagnosis. Standardized incidence ratios (SIR) compared risk between AYA survivors and general population. Age-period-cohort (APC) models examined trends over time. Fine and Gray's models identified therapy effects controlling for cancer and demographic confounders.

Results:

Of 374,408 survivors, 1,369 had an HPV-SMN, occurring on average 5 years after first cancer. Compared with the general population, AYA survivors had 70% increased risk for any HPV-SMN [95% confidence interval (CI), 1.61–1.79] and 117% for oropharyngeal-SMN (95% CI, 2.00–2.35); cervical-SMN risk was generally lower in survivors (SIR, 0.85; 95% CI, 0.76–0.95), but Hispanic AYA survivors had a 8.4 significant increase in cervical-SMN (SIR, 1.46; 95% CI, 1.01–2.06). AYAs first diagnosed with Kaposi sarcoma, leukemia, Hodgkin, and non-Hodgkin lymphoma had increased HPV-SMN risks compared with the general population. Oropharyngeal-SMN incidence declined over time in APC models. Chemotherapy and radiation were associated with any HPV-SMN among survivors with first HPV-related cancers, but not associated among survivors whose first cancers were not HPV-related.

Conclusions:

HPV-SMN in AYA survivors are driven by oropharyngeal cancers despite temporal declines in oropharyngeal-SMN. Hispanic survivors are at risk for cervical-SMN relative to the general population.

Impact:

Encouraging HPV vaccination and cervical and oral cancer screenings may reduce HPV-SMN burden among AYA survivors.
Fig S7 from Dynamics of Sequence and Structural Cell-Free DNA Landscapes in Small-Cell Lung Cancer
Authors: Sivapalan Lavanya , Iams Wade T. , Belcaid Zineb , Scott Susan C. , Niknafs Noushin , Balan Archana , White James R. , Kopparapu Prasad , Cann Christopher , Landon Blair V. , Pereira Gavin , Velculescu Victor E. , Hann Christine L. , Lovly Christine M. , Anagnostou Valsamo
Published: April 2023

Survival analyses of 31 patients with evaluable baseline plasma samples revealed that ctDNA molecular responses were significantly associated with both (A) overall survival-OS and (B) progression-free survival-PFS. Patients classified as molecular responders had a significantly longer OS and PFS compared to patients who were assigned a classification of molecular response f/b recrudescence or molecular progression. Comparison between molecular responses and radiographic assessments (PR/CR vs SD/PD/MR) in these patients revealed that ctDNA molecular responses were a stronger predictor of (C) OS at 12 and (D) 36 months and PFS at (E) 3 and (F) 12 months, compared to best overall radiographic responses.
Supplementary Figure S6 from Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in a Xenograft Model
Authors: Chen Shih-Shih , Barrientos Jacqueline C. , Ferrer Gerardo , King-Richards Morgan , Chen Yu-Ju , Ravichandran Priyadarshini , Ibrahim Michael , Kieso Yasmine , Waters Sheila , Kutok Jeffery L. , Peluso Marisa , Sharma Sujata , Weaver David T. , Pachter Jonathan A. , Rai Kanti R. , Chiorazzi Nicholas
Published: April 2023

Effects of treatment with duvelisib and ibrutinib on the numbers of T cells in in mice receiving samples from the same patients in Figure 6.
Supplementary Figure S4 from Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in a Xenograft Model
Authors: Chen Shih-Shih , Barrientos Jacqueline C. , Ferrer Gerardo , King-Richards Morgan , Chen Yu-Ju , Ravichandran Priyadarshini , Ibrahim Michael , Kieso Yasmine , Waters Sheila , Kutok Jeffery L. , Peluso Marisa , Sharma Sujata , Weaver David T. , Pachter Jonathan A. , Rai Kanti R. , Chiorazzi Nicholas
Published: April 2023

Distinct actions of PI3K-δ and PI3K-γ on human cytokines in PDX model of U-CLL and M-CLL patients.
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: April 2023

Distinct actions of PI3K-δ and PI3K-γ on numbers of immune cells in CLL.
Supplementary Figure S2 from Integrating Tumor-Intrinsic and Immunologic Factors to Identify Immunogenic Breast Cancers from a Low-Risk Cohort: Results from the Randomized SweBCG91RT Trial
Authors: Stenmark Tullberg Axel , Sjöström Martin , Niméus Emma , Killander Fredrika , Chang S. Laura , Feng Felix Y. , Speers Corey W. , Pierce Lori J. , Kovács Anikó , Lundstedt Dan , Holmberg Erik , Karlsson Per
Published: April 2023

Immunescore (A), developed in this manuscript, showed a stronger correlation with tumor-infiltrating lymphocytes than other developed methods (B and C) to quantify the degree of immune infiltration.
Data from Efficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations
Authors: Grant Michael J. , Aredo Jacqueline V. , Starrett Jacqueline H. , Stockhammer Paul , van Alderwerelt van Rosenburgh Iris K. , Wurtz Anna , Piper-Valillo Andrew J. , Piotrowska Zofia , Falcon Christina , Yu Helena A. , Aggarwal Charu , Scholes Dylan , Patil Tejas , Nguyen Christina , Phadke Manali , Li Fang-Yong , Neal Joel , Lemmon Mark A. , Walther Zenta , Politi Katerina , Goldberg Sarah B.
Published: April 2023

AbstractPurpose:
The uncommon EGFR exon 19 deletion (ex19del), L747_A750>P, demonstrates reduced sensitivity to osimertinib compared with the common ex19del, E746_A750del in preclinical models. The clinical efficacy of osimertinib in patients with non–small cell lung cancer harboring L747_A750>P and other uncommon ex19dels is not known.
Design:
The AACR GENIE database was interrogated to characterize the frequency of individual ex19dels relative to other variants, and a multicenter retrospective cohort was used to compare clinical outcomes for patients with tumors harboring E746_A750del, L747_A750>P, and other uncommon ex19dels who received osimertinib in the first line (1L) or in second or later lines of therapy and were T790M+ (≥2L).
Results:
ex19dels comprised 45% of EGFR mutations, with 72 distinct variants ranging in frequency from 28.1% (E746_A750del) to 0.03%, with L747_A750>P representing 1.8% of the EGFR mutant cohort. In our multi-institutional cohort (N = 200), E746_A750del was associated with significantly prolonged progression-free survival (PFS) with 1L osimertinib versus L747_A750>P [median 21.3 months (95% confidence interval, 17.0–31.7) vs. 11.7 months (10.8–29.4); adjusted HR 0.52 (0.28–0.98); P = 0.043]. Osimertinib efficacy in patients with other uncommon ex19dels varied on the basis of the specific mutation present.
Conclusions:
The ex19del L747_A750>P is associated with inferior PFS compared with the common E746_A750del mutation in patients treated with 1L osimertinib. Understanding differences in osimertinib efficacy among EGFR ex19del subtypes could alter management of these patients in the future.
Data from Integrating Tumor-Intrinsic and Immunologic Factors to Identify Immunogenic Breast Cancers from a Low-Risk Cohort: Results from the Randomized SweBCG91RT Trial
Authors: Stenmark Tullberg Axel , Sjöström Martin , Niméus Emma , Killander Fredrika , Chang S. Laura , Feng Felix Y. , Speers Corey W. , Pierce Lori J. , Kovács Anikó , Lundstedt Dan , Holmberg Erik , Karlsson Per
Published: April 2023

AbstractPurpose:
The local immune infiltrate's influence on tumor progression may be closely linked to tumor-intrinsic factors. The study aimed to investigate whether integrating immunologic and tumor-intrinsic factors can identify patients from a low-risk cohort who may be candidates for radiotherapy (RT) de-escalation.
Experimental Design:
The SweBCG91RT trial included 1,178 patients with stage I to IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median of 15.2 years. We trained two models designed to capture immunologic activity and immunomodulatory tumor-intrinsic qualities, respectively. We then analyzed if combining these two variables could further stratify tumors, allowing for identifying a subgroup where RT de-escalation is feasible, despite clinical indicators of a high risk of ipsilateral breast tumor recurrence (IBTR).
Results:
The prognostic effect of the immunologic model could be predicted by the tumor-intrinsic model (Pinteraction = 0.01). By integrating measurements of the immunologic- and tumor-intrinsic models, patients who benefited from an active immune infiltrate could be identified. These patients benefited from standard RT (HR, 0.28; 95% CI, 0.09–0.85; P = 0.025) and had a 5.4% 10-year incidence of IBTR after irradiation despite high-risk genomic indicators and a low frequency of systemic therapy. In contrast, high-risk tumors without an immune infiltrate had a high 10-year incidence of IBTR despite RT treatment (19.5%; 95% CI, 12.2–30.3).
Conclusions:
Integrating tumor-intrinsic and immunologic factors may identify immunogenic tumors in early-stage breast cancer populations dominated by ER-positive tumors. Patients who benefit from an activated immune infiltrate may be candidates for RT de-escalation.
Dynamics of Sequence and Structural Cell-Free DNA Landscapes in Small-Cell Lung Cancer
Authors: Sivapalan Lavanya , Iams Wade T. , Belcaid Zineb , Scott Susan C. , Niknafs Noushin , Balan Archana , White James R. , Kopparapu Prasad , Cann Christopher , Landon Blair V. , Pereira Gavin , Velculescu Victor E. , Hann Christine L. , Lovly Christine M. , Anagnostou Valsamo
Published: April 2023

Purpose:

Patients with small-cell lung cancer (SCLC) have an exceptionally poor prognosis, calling for improved real-time noninvasive biomarkers of therapeutic response.

Experimental Design:

We performed targeted error-correction sequencing on 171 serial plasmas and matched white blood cell (WBC) DNA from 33 patients with metastatic SCLC who received treatment with chemotherapy (n = 16) or immunotherapy-containing (n = 17) regimens. Tumor-derived sequence alterations and plasma aneuploidy were evaluated serially and combined to assess changes in total cell-free tumor load (cfTL). Longitudinal dynamic changes in cfTL were monitored to determine circulating cell-free tumor DNA (ctDNA) molecular response during therapy.

Results:

Combined tiered analyses of tumor-derived sequence alterations and plasma aneuploidy allowed for the assessment of ctDNA molecular response in all patients. Patients classified as molecular responders (n = 9) displayed sustained elimination of cfTL to undetectable levels. For 14 patients, we observed initial molecular responses, followed by ctDNA recrudescence. A subset of patients (n = 10) displayed a clear pattern of molecular progression, with persistence of cfTL across all time points. Molecular responses captured the therapeutic effect and long-term clinical outcomes in a more accurate and rapid manner compared with radiographic imaging. Patients with sustained molecular responses had longer overall (log-rank P = 0.0006) and progression-free (log-rank P < 0.0001) survival, with molecular responses detected on average 4 weeks earlier than imaging.

Conclusions:

ctDNA analyses provide a precise approach for the assessment of early on-therapy molecular responses and have important implications for the management of patients with SCLC, including the development of improved strategies for real-time tumor burden monitoring.

See related commentary by Pellini and Chaudhuri, p. 2176
Activating an Adaptive Immune Response with a Telomerase-Mediated Telomere Targeting Therapeutic in Hepatocellular Carcinoma
Authors: Mender Ilgen , Siteni Silvia , Barron Summer , Flusche Ann Marie , Kubota Naoto , Yu Chunhua , Cornelius Crystal , Tedone Enzo , Maziveyi Mazvita , Grichuk Anthony , Venkateswaran Niranjan , Conacci-Sorrell Maralice , Hoshida Yujin , Kang Rui , Tang Daolin , Gryaznov Sergei , Shay Jerry W.
Published: April 2023

A select group of patients with hepatocellular carcinomas (HCC) benefit from surgical, radiologic, and systemic therapies that include a combination of anti-angiogenic and immune-checkpoint inhibitors. However, because HCC is generally asymptomatic in its early stages, this not only leads to late diagnosis, but also to therapy resistance. The nucleoside analogue 6-thio-dG (THIO) is a first-in-class telomerase-mediated telomere-targeting anticancer agent. In telomerase expressing cancer cells, THIO is converted into the corresponding 5′-triphosphate, which is efficiently incorporated into telomeres by telomerase, activating telomere damage responses and apoptotic pathways. Here, we show how THIO is effective in controlling tumor growth and, when combined with immune checkpoint inhibitors, is even more effective in a T-cell-dependent manner. We also show telomere stress induced by THIO increases both innate sensing and adaptive antitumor immunity in HCC. Importantly, the extracellular high-mobility group box 1 protein acts as a prototypical endogenous DAMP (Damage Associated Molecular Pattern) in eliciting adaptive immunity by THIO. These results provide a strong rationale for combining telomere-targeted therapy with immunotherapy.
Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma
Authors: Hoppe Michal Marek , Jaynes Patrick , Shuangyi Fan , Peng Yanfen , Sridhar Shruti , Hoang Phuong Mai , Liu Clementine Xin , De Mel Sanjay , Poon Limei , Chan Esther Hian Li , Lee Joanne , Ong Choon Kiat , Tang Tiffany , Lim Soon Thye , Nagarajan Chandramouli , Grigoropoulos Nicholas F. , Tan Soo-Yong , Hue Susan Swee-Shan , Chang Sheng-Tsung , Chuang Shih-Sung , Li Shaoying , Khoury Joseph D. , Choi Hyungwon , Harris Carl , Bottos Alessia , Gay Laura J. , Runge Hendrik F.P. , Moutsopoulos Ilias , Mohorianu Irina , Hodson Daniel J. , Farinha Pedro , Mottok Anja , Scott David W. , Pitt Jason J. , Chen Jinmiao , Kumar Gayatri , Kannan Kasthuri , Chng Wee Joo , Chee Yen Lin , Ng Siok-Bian , Tripodo Claudio , Jeyasekharan Anand D.
Published: April 2023

Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6− (M+2+6−) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6− percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n = 316) and gene expression (n = 2,521) datasets. Comparative bulk/single-cell transcriptomic analyses of DLBCL samples and MYC/BCL2/BCL6-transformed primary B cells identify molecular features, including cyclin D2 and PI3K/AKT as candidate regulators of M+2+6− unfavorable biology. Similar analyses evaluating oncogenic combinations at single-cell resolution in other cancers may facilitate an understanding of cancer evolution and therapy resistance.

Significance:

Using single-cell–resolved multiplexed imaging, we show that selected subpopulations of cells expressing specific combinations of oncogenes influence clinical outcomes in lymphoma. We describe a probabilistic metric for the estimation of cellular oncogenic coexpression from IHC or bulk transcriptomes, with possible implications for prognostication and therapeutic target discovery in cancer.

This article is highlighted in the In This Issue feature, p. 1027
The Polyamine–Hypusine Circuit Controls an Oncogenic Translational Program Essential for Malignant Conversion in MYC-Driven Lymphoma
Authors: Nakanishi Shima , Li Jiannong , Berglund Anders E. , Kim Youngchul , Zhang Yonghong , Zhang Ling , Yang Chunying , Song Jinming , Mirmira Raghavendra G. , Cleveland John L.
Published: April 2023

The MYC oncoprotein is activated in a broad spectrum of human malignancies and transcriptionally reprograms the genome to drive cancer cell growth. Given this, it is unclear if targeting a single effector of MYC will have therapeutic benefit. MYC activates the polyamine–hypusine circuit, which posttranslationally modifies the eukaryotic translation factor eIF5A. The roles of this circuit in cancer are unclear. Here we report essential intrinsic roles for hypusinated eIF5A in the development and maintenance of MYC-driven lymphoma, where the loss of eIF5A hypusination abolishes malignant transformation of MYC-overexpressing B cells. Mechanistically, integrating RNA sequencing, ribosome sequencing, and proteomic analyses revealed that efficient translation of select targets is dependent upon eIF5A hypusination, including regulators of G1–S phase cell-cycle progression and DNA replication. This circuit thus controls MYC's proliferative response, and it is also activated across multiple malignancies. These findings suggest the hypusine circuit as a therapeutic target for several human tumor types.

Significance:

Elevated EIF5A and the polyamine–hypusine circuit are manifest in many malignancies, including MYC-driven tumors, and eIF5A hypusination is necessary for MYC proliferative signaling. Not­ably, this circuit controls an oncogenic translational program essential for the development and maintenance of MYC-driven lymphoma, supporting this axis as a target for cancer prevention and treatment.

See related commentary by Wilson and Klein, p. 248.

This article is highlighted in the In This Issue feature, p. 247
Figure S9 from Identification of Membrane-expressed CAPRIN-1 as a Novel and Universal Cancer Target, and Generation of a Therapeutic Anti-CAPRIN-1 Antibody TRK-950
Authors: Okano Fumiyoshi , Saito Takanori , Minamida Yoshitaka , Kobayashi Shinichi , Ido Takayoshi , Miyauchi Yasushi , Wasai Ukei , Akazawa Daisuke , Kume Masahiko , Ishibashi Masaki , Jiang Ke , Aicher Alexandra , Heeschen Christopher , Yonehara Tetsu
Published: April 2023

ADCC and ADCP activity of TRK-950 via human and monkey immune cells
Supplementary Tables 1-5 from Integrative metatranscriptomic analysis reveals disease-specific microbiome-host interactions in oral squamous cell carcinoma
Authors: Jain Vinay , Baraniya Divyashri , Elhadedy Doaa E , Chen Tsute , Slifker Michael J. , Alakwaa Fadhl , Cai Kathy Q. , Chitrala Kumaraswamy Naidu , Fundakowski Christopher , Al-hebshi Nezar
Published: April 2023

Word document with Supplementary Tables 1-5
Supplementary File 2 from Integrative metatranscriptomic analysis reveals disease-specific microbiome-host interactions in oral squamous cell carcinoma
Authors: Jain Vinay , Baraniya Divyashri , Elhadedy Doaa E , Chen Tsute , Slifker Michael J. , Alakwaa Fadhl , Cai Kathy Q. , Chitrala Kumaraswamy Naidu , Fundakowski Christopher , Al-hebshi Nezar
Published: April 2023

Detailed sequencing and mapping statistics.
Supplementary Figures 1-12 from Integrative metatranscriptomic analysis reveals disease-specific microbiome-host interactions in oral squamous cell carcinoma
Authors: Jain Vinay , Baraniya Divyashri , Elhadedy Doaa E , Chen Tsute , Slifker Michael J. , Alakwaa Fadhl , Cai Kathy Q. , Chitrala Kumaraswamy Naidu , Fundakowski Christopher , Al-hebshi Nezar
Published: April 2023

PDF document with Supplementary Figures 1-12
Identification of Membrane-expressed CAPRIN-1 as a Novel and Universal Cancer Target, and Generation of a Therapeutic Anti-CAPRIN-1 Antibody TRK-950
Authors: Okano Fumiyoshi , Saito Takanori , Minamida Yoshitaka , Kobayashi Shinichi , Ido Takayoshi , Miyauchi Yasushi , Wasai Ukei , Akazawa Daisuke , Kume Masahiko , Ishibashi Masaki , Jiang Ke , Aicher Alexandra , Heeschen Christopher , Yonehara Tetsu
Published: April 2023

Specific targets for cancer treatment are highly desirable, but still remain to be discovered. While previous reports suggested that CAPRIN-1 localizes in the cytoplasm, here we now show that part of this molecule is strongly expressed on the cell membrane surface in most solid cancers, but not normal tissues. Notably, the membrane expression of CAPRIN-1 extended to the subset of highly tumorigenic cancer stem cells and epithelial–mesenchymal transition (EMT)–induced metastatic cancer cells. In addition, we revealed that cancer cells with particularly high CAPRIN-1 surface expression exhibited enhanced tumorigenicity. We generated a therapeutic humanized anti-CAPRIN-1 antibody (TRK-950), which strongly and specifically binds to various cancer cells and shows antitumor effects via engagement of immune cells. TRK-950 was further developed as a new cancer drug and a series of preclinical studies demonstrates its therapeutic potency in tumor-bearing mouse models and safety in a relevant cynomolgus monkey model. Together, our data demonstrate that CAPRIN-1 is a novel and universal target for cancer therapies. A phase I clinical study of TRK-950 has been completed (NCT02990481) and a phase Ib study (combination with approved drugs) is currently underway (NCT03872947) in the United States and France. In parallel, a phase I study in Japan is in progress as well (NCT05423262).

Significance:

Antibody-based cancer therapies have been demonstrated to be effective, but are only approved for a limited number of targets, because the majority of these markers is shared with healthy tissue, which may result in adverse effects. Here, we have successfully identified CAPRIN-1 as a novel truly cancer-specific target, universally expressed on membranes of various cancer cells including cancer stem cells. Clinical studies are underway for the anti-CAPRIN-1 therapeutic antibody TRK-950.
Integrative Metatranscriptomic Analysis Reveals Disease-specific Microbiome–host Interactions in Oral Squamous Cell Carcinoma
Authors: Jain Vinay , Baraniya Divyashri , El-Hadedy Doaa E. , Chen Tsute , Slifker Michael , Alakwaa Fadhl , Cai Kathy Q. , Chitrala Kumaraswamy N. , Fundakowski Christopher , Al-Hebshi Nezar N.
Published: April 2023

Studies on the microbiome of oral squamous cell carcinoma (OSCC) have been limited to 16S rRNA gene sequencing. Here, laser microdissection coupled with brute-force, deep metatranscriptome sequencing was employed to simultaneously characterize the microbiome and host transcriptomes and predict their interaction in OSCC. The analysis involved 20 HPV16/18-negative OSCC tumor/adjacent normal tissue pairs (TT and ANT) along with deep tongue scrapings from 20 matched healthy controls (HC). Standard bioinformatic tools coupled with in-house algorithms were used to map, analyze, and integrate microbial and host data. Host transcriptome analysis identified enrichment of known cancer-related gene sets, not only in TT versus ANT and HC, but also in the ANT versus HC contrast, consistent with field cancerization. Microbial analysis identified a low abundance yet transcriptionally active, unique multi-kingdom microbiome in OSCC tissues predominated by bacteria and bacteriophages. HC showed a different taxonomic profile yet shared major microbial enzyme classes and pathways with TT/ANT, consistent with functional redundancy. Key taxa enriched in TT/ANT compared with HC were Cutibacterium acnes, Malassezia restricta, Human Herpes Virus 6B, and bacteriophage Yuavirus. Functionally, hyaluronate lyase was overexpressed by C. acnes in TT/ANT. Microbiome-host data integration revealed that OSCC-enriched taxa were associated with upregulation of proliferation-related pathways. In a preliminary in vitro validation experiment, infection of SCC25 oral cancer cells with C. acnes resulted in upregulation of MYC expression. The study provides a new insight into potential mechanisms by which the microbiome can contribute to oral carcinogenesis, which can be validated in future experimental studies.

Significance:

Studies have shown that a distinct microbiome is associated with OSCC, but how the microbiome functions within the tumor interacts with the host cells remains unclear. By simultaneously characterizing the microbial and host transcriptomes in OSCC and control tissues, the study provides novel insights into microbiome-host interactions in OSCC which can be validated in future mechanistic studies.
African American Prostate Cancer Displays Quantitatively Distinct Vitamin D Receptor Cistrome-transcriptome Relationships Regulated by BAZ1A
Authors: Siddappa Manjunath , Hussain Shahid , Wani Sajad A. , White Jason , Tang Hancong , Gray Jaimie S. , Jafari Hedieh , Wu Hsu-Chang , Long Mark D. , Elhussin Isra , Karanam Balasubramanyam , Wang Honghe , Morgan Rebecca , Hardiman Gary , Adelani Isaacson B. , Rotimi Solomon O. , Murphy Adam R. , Nonn Larisa , Davis Melissa B. , Kittles Rick A. , Hughes Halbert Chanita , Sucheston-Campbell Lara E. , Yates Clayton , Campbell Moray J.
Published: April 2023

African American (AA) prostate cancer associates with vitamin D3 deficiency, but vitamin D receptor (VDR) genomic actions have not been investigated in this context. We undertook VDR proteogenomic analyses in European American (EA) and AA prostate cell lines and four clinical cohorts. Rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) analyses revealed that nonmalignant AA RC43N prostate cells displayed the greatest dynamic protein content in the VDR complex. Likewise, in AA cells, Assay for Transposase-Accessible Chromatin using sequencing established greater 1α,25(OH)2D3-regulated chromatin accessibility, chromatin immunoprecipitation sequencing revealed significant enhancer-enriched VDR cistrome, and RNA sequencing identified the largest 1α,25(OH)2D3-dependent transcriptome. These VDR functions were significantly corrupted in the isogenic AA RC43T prostate cancer cells, and significantly distinct from EA cell models. We identified reduced expression of the chromatin remodeler, BAZ1A, in three AA prostate cancer cohorts as well as RC43T compared with RC43N. Restored BAZ1A expression significantly increased 1α,25(OH)2D3-regulated VDR-dependent gene expression in RC43T, but not HPr1AR or LNCaP cells. The clinical impact of VDR cistrome-transcriptome relationships were tested in three different clinical prostate cancer cohorts. Strikingly, only in AA patients with prostate cancer, the genes bound by VDR and/or associated with 1α,25(OH)2D3-dependent open chromatin (i) predicted progression from high-grade prostatic intraepithelial neoplasia to prostate cancer; (ii) responded to vitamin D3 supplementation in prostate cancer tumors; (iii) differentially responded to 25(OH)D3 serum levels. Finally, partial correlation analyses established that BAZ1A and components of the VDR complex identified by RIME significantly strengthened the correlation between VDR and target genes in AA prostate cancer only. Therefore, VDR transcriptional control is most potent in AA prostate cells and distorted through a BAZ1A-dependent control of VDR function.

Significance:

Our study identified that genomic ancestry drives the VDR complex composition, genomic distribution, and transcriptional function, and is disrupted by BAZ1A and illustrates a novel driver for AA prostate cancer.