bluuebunny/crossref_metadata_2025 huggingface dataset:
A Generalized Framework for the Alternate Load Path Redundancy Analysis of Steel Truss Bridges Subjected to Sudden Member Loss Scenarios
Authors: Li Huihui , Shen Lian , Deng Shuwen
Published: October 2022

Owing to their distinct features, such as structural simplicity and excellent load-carrying capacity, steel truss bridges are widely applied as critical transportation networks. However, many previously designed steel truss bridges that are located in harsh environmental conditions are facing severe challenges of overloading and aging or deteriorating critical structural members due to increasing traffic load and corrosion problems (i.e., chloride-induced corrosion). As a consequence, these overloaded and deteriorated critical members may initialize localized damage (e.g., sudden member failure scenarios) and then trigger a disproportionate collapse (i.e., progressive collapse) of steel truss bridges. To this end, to protect the steel truss bridges from progressive collapse resulting from locally induced damages (e.g., sudden removal of a critical member), this paper proposed a generalized framework to identify the critical members and to qualify the alternate load path (ALP) redundancy of steel truss bridges subjected to sudden member loss of a critical member. Demand-to-capacity ratio (DCR) for linear elastic analysis and strain ratio (SR) for nonlinear dynamic analysis were employed as the design metrics and performance indicators to qualify the ALP redundancy of steel truss bridges. Effectiveness of the proposed framework in qualifying the ALP redundancy of steel truss bridges was demonstrated through the I-35W truss bridge under sudden member removal (MR) analyses. Results obtained from this study may provide beneficial information and could serve as good references for the protection of steel truss bridges that are vulnerable to sudden member loss scenarios.
Fracture Mechanical Properties of Steel Fiber Reinforced Self-Compacting Concrete under Dry–Wet Cycle Sulfate Attack
Authors: Liu Junxia , Zang Shujie , Yang Fei , Zhang Maoliang , Li Anbang
Published: October 2022

Sulfate attack is the most common form of the durability damage of hydraulic concrete, and the performance degradation of cracked structural components is more significant at the position of water level change. Fly ash, a widely utilized supplementary cementitious material, can effectively improve the durability of concrete. In this paper, fly ash was used to partially replace Portland cement at 0 w%, 40 w%, 50 w%, 60 w%, and 70 w%, respectively. Through the three-point bending beam test with notch and the dry–wet cycle of sulfate attack, the change law of the fly ash content on the fracture mechanical properties of steel fiber reinforced self-compacting concrete (SFSCC) and its degradation mechanism under sulfate attack was studied. The results show that the load–crack mouth opening displacement curve of SFSCC changed from a steamed bread peak to a sharp peak under 30 dry–wet cycles of sulfate attack. The fracture toughness, peak load, and fracture energy of SFSCC with a high-volume fly ash increased with the increase in the fly ash content, while they reversed after sulfate attack. When the percentage of fly ash was 70 w%, the retention ratio of the fracture parameters was lower than that of SFSCC without incorporating fly ash, and when the percentage of fly ash was 50 w%, SFSCC had good bearing capacity, fracture mechanical properties, and corrosion resistance. The corrosion product of the reference SFSCC with 30 dry–wet cycles of sulfate attack was ettringite, whereas the SFSCC with a high-volume fly ash had no obvious corrosion products and the microstructure became looser.
Influence of the Jeziorsko Dam Reservoir on Water Flow in the Warta River
Authors: Nowak Bogumił , Ptak Mariusz , Szyga-Pluta Katarzyna , Sojka Mariusz
Published: October 2022

The progressing development of civilisation and climate change require access to an appropriate quantity of environmental resources. One of the key resources is water. Both its deficit and excess evidently affect human life. Control over water circulation is possible owing to water management, largely involving introduction of hydraulic structures. The paper analyses the effect of the Jeziorsko dam reservoir on the flows of the Warta River, the third largest river in Poland. It analyses water flows in the Warta River in the years 1993–2020 for hydrological stations above and below the reservoir. The conducted research showed that the construction of the Jeziorsko reservoir also substantially contributed to an increase in minimum flows and a decrease in maximum flows. Moreover, the simulation showed that in the case of abscence of the reservoir, the flows of the Warta River would be higher in the period from January to June, and in the period from July to October the opposite situation would occur. In November and December, the flows would be at a similar level. Results obtained in the study, show that hydraulic structures are an effective solution in the context of stabilisation of the hydrological situation in a given region, particularly in terms of hydrological lows occurring with increasing intensity mitigated on sections of rivers below the reservoirs.
Evaluating the Role of Nigerian Bankruptcy Law in Enhancing Female Entrepreneurship in Nigeria
Authors: Adepoju Omoseni , Nwulu Tobi , David Love
Published: October 2022

The study focused on the role of Nigerian bankruptcy law in fostering female entrepreneurship. The study examined how the current bankruptcy law supports female entrepreneurship in Nigeria. This was motivated by the Nigerian government’s recent entrepreneurship drive to meet the country’s excessive challenge of unemployment and poverty. Five principles were utilised in this study to measure current Nigerian bankruptcy law to evaluate its effect on the female entrepreneurship drive in Nigeria. The study adopted a qualitative research methodology to evaluate legal doctrines and relevant literatures. The study’s findings revealed that the present Nigerian bankruptcy law is not entirely favourable to female entrepreneurship. This conclusion was arrived at having measured the Nigerian bankruptcy law against five testable principles. These principles were developed to help as a guide in measuring bankruptcy laws to determine whether they are entrepreneur-friendly. In light of this, recommendations were proffered to reform the current bankruptcy law to introduce better policies that enhance female entrepreneurship.
Treatment of Indolent Cutaneous B-Cell Lymphoma with Intralesional or Intravenous Rituximab
Authors: Menzer Christian , Rendon Adriana , Hassel Jessica C.
Published: October 2022

Indolent cutaneous B-cell lymphomas (CBCL) are a rare disease for which the therapeutic recommendations are based on clinical reports. Recommendations for solitary lesions include surgery or irradiation. However, the high relapse rates may require less invasive repeatable therapy. This study seeks to retrospectively assess the efficacy of intralesional rituximab (ILR) for indolent CBCL when compared with intravenous rituximab (IVR). Patients treated for indolent CBCL with ILR or IVR at the Division of DermatoOncology of the University Hospital Heidelberg were eligible for this study. Characteristics of lymphoma, treatment response, and adverse events were assessed. Twenty-one patients, 67% male at a median age of 52 (range 17–80), were included. Nineteen (90%) had only localized lymphoma (stage T1 and T2). Complete response was achieved in 92% (11/12) of ILR after a median of one cycle (three injections) and 78% (7/8) of IVR patients after a median of six cycles. Half of ILR patients and 78% of IVR patients showed relapse after a median of 15 and 23 months, respectively. Adverse reactions were usually mild and were limited to the first injection of ILR. One patient with IVR contracted a pulmonary infection. ILR may be an alternative to the intravenous administration of rituximab for localized indolent CBCL.
Surgical Treatment of Spinal Meningiomas in the Elderly (≥75 Years): Which Factors Affect the Neurological Outcome? An International Multicentric Study of 72 Cases
Authors: Capo Gabriele , Moiraghi Alessandro , Baro Valentina , Tahhan Nadim , Delaidelli Alberto , Saladino Andrea , Paun Luca , DiMeco Francesco , Denaro Luca , Meling Torstein Ragnar , Tessitore Enrico , Barrey Cédric Yves
Published: October 2022

(1) Background: With the increasing life expectancy in the Western world, an increasing number of old patients presents with spinal meningioma. Considering the benign nature of these tumors, the functional outcome remains of great importance, since more people reach old age in general conditions of well-being and satisfactory autonomy. (2) Methods: We conducted an international multicenter retrospective study to investigate demographic, clinical and radiological data in a population of elderly patients (≥75 years of age) undergoing surgery for SM from January 2000 to December 2020 in four European referral centers. The aim was to identify prognostic and predictive factors for a good postoperative functional outcome. (3) Results: 72 patients were included in the study. Complete tumor resection (Simpson I or II) was achieved in 67 (95.7%) cases. Intraoperative complications were reported in 7 (9.9%) patients while postoperative complications were found in 12 (16.7%). An excellent general postoperative status (McCormick I and II) was achieved in 65.3%. Overall, surgical resection had a good impact on patients’ functional outcome (86.1% either showing an improvement or maintaining a good preoperative status). Uni- and multivariate analyses found that both age and preoperative modified McCormick independently correlated with relative outcome (coeff = −0.058, p = 0.0251; coeff = 0.597, p < 0.0001) and with postoperative status (coeff = 0.058, p = 0.02507; coeff = 0.402, p = 0.00027), respectively. (4) Conclusions: Age and preoperative modified McCormick were found to be independent prognostic factors. Nevertheless, advanced age (≥75), per se, did not seem to contraindicate surgery, even in those with severe preoperative neurological deficits. The functional results sustain the need for surgical resection of SM in the elderly.
Modulation of Plasma Lipidomic Profiles in Metastatic Castration-Resistant Prostate Cancer by Simvastatin
Authors: Mak Blossom , Lin Hui-Ming , Duong Thy , Mahon Kate L. , Joshua Anthony M. , Stockler Martin R. , Gurney Howard , Parnis Francis , Zhang Alison , Scheinberg Tahlia , Wittert Gary , Butler Lisa M. , Sullivan David , Hoy Andrew J. , Meikle Peter J. , Horvath Lisa G.
Published: October 2022

Elevated circulating sphingolipids are associated with shorter overall survival and therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC), suggesting that perturbations in sphingolipid metabolism promotes prostate cancer growth. This study assessed whether addition of simvastatin to standard treatment for mCRPC can modify a poor prognostic circulating lipidomic profile represented by a validated 3-lipid signature (3LS). Men with mCRPC (n = 27) who were not on a lipid-lowering agent, were given simvastatin for 12 weeks (40 mg orally, once daily) with commencement of standard treatment. Lipidomic profiling was performed on their plasma sampled at baseline and after 12 weeks of treatment. Only 11 men had the poor prognostic 3LS at baseline, of whom five (45%) did not retain the 3LS after simvastatin treatment (expected conversion rate with standard treatment = 19%). At baseline, the plasma profiles of men with the 3LS displayed higher levels (p < 0.05) of sphingolipids (ceramides, hexosylceramides and sphingomyelins) than those of men without the 3LS. These plasma sphingolipids were reduced after statin treatment in men who lost the 3LS (mean decrease: 23–52%, p < 0.05), but not in men with persistent 3LS, and were independent of changes to plasma cholesterol, LDL-C or triacylglycerol. In conclusion, simvastatin in addition to standard treatment can modify the poor prognostic circulating lipidomic profile in mCRPC into a more favourable profile at twice the expected conversion rate.
External Validation of a Mammography-Derived AI-Based Risk Model in a U.S. Breast Cancer Screening Cohort of White and Black Women
Authors: Gastounioti Aimilia , Eriksson Mikael , Cohen Eric A. , Mankowski Walter , Pantalone Lauren , Ehsan Sarah , McCarthy Anne Marie , Kontos Despina , Hall Per , Conant Emily F.
Published: October 2022

Despite the demonstrated potential of artificial intelligence (AI) in breast cancer risk assessment for personalizing screening recommendations, further validation is required regarding AI model bias and generalizability. We performed external validation on a U.S. screening cohort of a mammography-derived AI breast cancer risk model originally developed for European screening cohorts. We retrospectively identified 176 breast cancers with exams 3 months to 2 years prior to cancer diagnosis and a random sample of 4963 controls from women with at least one-year negative follow-up. A risk score for each woman was calculated via the AI risk model. Age-adjusted areas under the ROC curves (AUCs) were estimated for the entire cohort and separately for White and Black women. The Gail 5-year risk model was also evaluated for comparison. The overall AUC was 0.68 (95% CIs 0.64–0.72) for all women, 0.67 (0.61–0.72) for White women, and 0.70 (0.65–0.76) for Black women. The AI risk model significantly outperformed the Gail risk model for all women p < 0.01 and for Black women p < 0.01, but not for White women p = 0.38. The performance of the mammography-derived AI risk model was comparable to previously reported European validation results; non-significantly different when comparing White and Black women; and overall, significantly higher than that of the Gail model.
Emergence of MUC1 in Mammals for Adaptation of Barrier Epithelia
Authors: Kufe Donald W.
Published: October 2022

The mucin 1 (MUC1) gene was discovered based on its overexpression in human breast cancers. Subsequent work demonstrated that MUC1 is aberrantly expressed in cancers originating from other diverse organs, including skin and immune cells. These findings supported a role for MUC1 in the adaptation of barrier tissues to infection and environmental stress. Of fundamental importance for this evolutionary adaptation was inclusion of a SEA domain, which catalyzes autoproteolysis of the MUC1 protein and formation of a non-covalent heterodimeric complex. The resulting MUC1 heterodimer is poised at the apical cell membrane to respond to loss of homeostasis. Disruption of the complex releases the MUC1 N-terminal (MUC1-N) subunit into a protective mucous gel. Conversely, the transmembrane C-terminal (MUC1-C) subunit activates a program of lineage plasticity, epigenetic reprogramming and repair. This MUC1-C-activated program apparently evolved for barrier tissues to mount self-regulating proliferative, inflammatory and remodeling responses associated with wound healing. Emerging evidence indicates that MUC1-C underpins inflammatory adaptation of tissue stem cells and immune cells in the barrier niche. This review focuses on how prolonged activation of MUC1-C by chronic inflammation in these niches promotes the cancer stem cell (CSC) state by establishing auto-inductive nodes that drive self-renewal and tumorigenicity.
Novel Small Multilamellar Liposomes Containing Large Quantities of Peptide Nucleic Acid Selectively Kill Breast Cancer Cells
Authors: Proshkina Galina , Shramova Elena , Ryabova Anastasiya , Katrivas Liat , Giannini Clelia , Malpicci Daniele , Levi-Kalisman Yael , Deyev Sergey , Kotlyar Alexander
Published: October 2022

Peptide nucleic acid (PNA) may be used in various biomedical applications; however, these are currently limited, due to its low solubility in aqueous solutions. In this study, a methodology to overcome this limitation is demonstrated, as well as the effect of PNA on cell viability. We show that extruding a mixture of natural phospholipids and short (6–22 bases), cytosine-rich PNA through a 100 nm pore size membrane under mild acidic conditions resulted in the formation of small (60–90 nm in diameter) multilamellar vesicles (SMVs) comprising several (3–5) concentric lipid membranes. The PNA molecules, being positively charged under acidic conditions (due to protonation of cytosine bases in the sequence), bind electrostatically to negatively charged phospholipid membranes. The large membrane surface area allowed the encapsulation of thousands of PNA molecules in the vesicle. SMVs were conjugated with the designed ankyrin repeat protein (DARPin_9-29), which interacts with human epidermal growth factor receptor 2 (HER2), overexpressed in human breast cancer. The conjugate was shown to enter HER2-overexpressing cells by receptor-mediated endocytosis. PNA molecules, released from lysosomes, aggregate in the cytoplasm into micron-sized particles, which interfere with normal cell functioning, causing cell death. The ability of DARPin-functionalized SMVs to specifically deliver large quantities of PNA to cancer cells opens a new promising avenue for cancer therapy.
TFAP2C Knockdown Sensitizes Bladder Cancer Cells to Cisplatin Treatment via Regulation of EGFR and NF-κB
Authors: Xing Ji , Chen Wu , Chen Kang , Zhu Shaoming , Lin Fangyou , Qi Yucheng , Zhang Yunlong , Han Shangting , Rao Ting , Ruan Yuan , Zhao Sheng , Yu Weimin , Cheng Fan
Published: October 2022

Cisplatin is the first-line chemotherapy for advanced or metastatic bladder cancer. Nevertheless, approximately half of patients with BCa are insensitive to cisplatin therapy or develop cisplatin resistance during the treatment process. Therefore, it is especially crucial to investigate ways to enhance the sensitivity of tumor cells to cisplatin. Transcription factor AP-2 gamma (TFAP2C) is involved in cancer development and chemotherapy sensitivity. However, its relationship with chemotherapy has not been studied in BCa. In this study, we aimed to investigate the therapeutic potential of TFAP2C in human BCa. Results based on TCGA (The Cancer Genome Atlas), GTEx (The Genotype-Tissue Expression) and GEO (Gene Expression Omnibus) data showed that TFAP2C expression was upregulated in BCa tissues and that its high expression was associated with poor prognosis. Meanwhile, we demonstrated the overexpression of TFAP2C in BCa clinical specimens. Subsequently, in vitro, we knocked down TFAP2C in BCa cells and found that TFAP2C knockdown further increased cell cycle arrest and apoptosis caused by cisplatin. In addition, the inhibitory effect of cisplatin on BCa cell migration and invasion was enhanced by TFAP2C knockdown. Our data indicated that cisplatin increased epidermal growth factor receptor (EGFR) and nuclear factor-kappaB (NF-κB) activation levels, but TFAP2C knockdown suppressed this effect. Finally, in vivo data further validated these findings. Our study showed that TFAP2C knockdown affected the activation levels of EGFR and NF-κB and enhanced the anti-tumor effects of cisplatin in vivo and in vitro. This provides a new direction to improve the efficacy of traditional cisplatin chemotherapy.
SIPA1 Regulates LINC01615 to Promote Metastasis in Triple-Negative Breast Cancer
Authors: Xiang Yuan , Feng Lingyun , Liu Hui , Liu Yuhuan , Li Jiapeng , Su Li , Liao Xinghua
Published: October 2022

Long non-coding RNAs (lncRNAs) are reported to play an important regulatory effect in carcinogenesis and malignancy. We found by high-throughput sequencing that LINC01615 is upregulated in breast cancer patients and reduces patients’ overall survival. In vivo and in vitro experiments, we clarified that overexpression of LINC01615 can promote breast cancer cell metastasis ability. The expression of LINC01615 is regulated by the transcriptional activator SIPA1, thereby promoting carcinogenesis in breast cancer cells. Our research clarified that LINC01615 can act as an oncogenic factor in promoting the development of breast cancer.
Health Burdens and SES in Alabama: Using Geographic Information System to Examine Prostate Cancer Health Disparity
Authors: Aladuwaka Seela , Alagan Ram , Singh Rajesh , Mishra Manoj
Published: October 2022

Socioeconomic disparities influence the risk of many diseases, including cancer. The cancer rate in Alabama is high, and the state has one of the highest rates of prostate cancer in the USA. Alabama’s counties are embedded with socioeconomic disparities, politics, race, ethnicity, and oppression, among which social equity and socioeconomic status (SES) been closely associated with prostate cancer. The Geographic Information System (GIS) has become a valuable technology in understanding public health in many applications, including cancer. This study integrates Alabama’s county-level prostate cancer incidence and mortality and its association with socioeconomic and health disparities. We conducted robust data mining from several data sources such as the Alabama State Cancer Profile data, Alabama Department of Health, American Cancer Society, Center for Disease Control, and National Cancer Institute. The research method is the Geographic Information System (GIS), and we employed prostate cancer data within GIS to understand Alabama’s prostate cancer prevalence regarding SES. The GIS analysis indicated an apparent socioeconomic disparity between the Black Belt and Non-Black Belt counties of Alabama. The Black Belt counties’ poverty rate is also remarkably higher than non-Black Belt counties. In addition, we analyzed the median household income by race. Our analysis demonstrates that the Asian background population in the state earned the highest median income compared to non-Hispanic whites and the African American population. Furthermore, the data revealed that the preexisting condition of diabetes and obesity is closely associated with prostate cancer. The GIS analysis suggests that prostate cancer incidence and mortality disparities are strongly related to SES. In addition, the preexisting condition of obesity and diabetes adds to prostate cancer incidences. Poverty also reflects inequalities in education, income, and healthcare facilities, particularly among African Americans, contributing to Alabama’s health burden of prostate cancer.
H3F3A K27M Mutation Promotes the Infiltrative Growth of High-Grade Glioma in Adults by Activating β-Catenin/USP1 Signaling
Authors: Sun Zhiyuan , Zhu Yufu , Feng Xia , Liu Xiaoyun , Zhou Kunlin , Wang Qing , Zhang Hengzhu , Shi Hengliang
Published: October 2022

H3F3A K27M (H3.3K27M) is a newly identified molecular pathological marker in glioma and is strongly correlated with the malignancy of diffuse intrinsic pontine glioma (DIPG). In recent years, accumulating evidence has revealed that other types of glioma also contain the H3.3K27M mutation. However, the role of H3.3K27M in high-grade adult glioma, the most malignant glioma, has not been investigated. In this study, we focused on exploring the expression and function of H3.3K27M in high-grade glioma in adults. We found that H3.3K27M was highly expressed at high levels in some high-grade glioma tissues. Then, we introduced H3.3K27M into H3.3 wild-type glioma cells, U87 cells and LN229 cells. We found that H3.3K27M did not affect the growth of glioma cells in vitro and in vivo; however, the survival of mice with transplanted tumors was significantly reduced. Further investigation revealed that H3.3K27M expression mainly promoted the migration and invasion of glioma cells. Moreover, we confirmed that H3.3K27M overexpression increased the levels of the β-catenin and p-β-catenin (Ser675) proteins, the ubiquitin-specific protease 1 (USP1) mRNA and protein levels, and the enhancer of zeste homolog 2 (EZH2) protein level. In addition, the β-catenin inhibitor XAV-939 significantly attenuated the upregulation of the aforementioned proteins and inhibited the increased migration and invasion caused by the H3.3K27M mutation. Overall, the H3.3K27M mutation in high-grade glioma is a potential biomarker for poor prognosis mainly due to the infiltration of glioma cells that is at least partially mediated by the β-catenin/USP1/EZH2 pathway.
Image-Guided Brachytherapy for Rectal Cancer: Reviewing the Past Two Decades of Clinical Investigation
Authors: Vuong Te , Garant Aurelie , Vendrely Veronique , Nout Remi , Martin André-Guy , Enger Shirin A. , Podgorsak Ervin , Moftah Belal , Devic Slobodan
Published: October 2022

(1) Background: The introduction of total mesorectal excision (TME) for rectal cancer has led to improvement in local recurrence (LR) outcomes. Furthermore, the addition of preoperative external beam radiotherapy to TME reduces LR to less than 6%. As a trade-off to these gradual improvements in local therapies, the oncology community’s work is now focusing on mitigating treatment-related toxicities. In other words, if a small proportion of 4–6% of rectal cancer patients benefit from additional local therapy beyond TME, the burden of acute and long-term side effects must be considered with care. (2) Methods: With the introduction of better-quality imaging for tumor visualization and treatment planning, a new conformed radiation treatment was introduced with high-dose-rate endorectal brachytherapy. The treatment concept was tested in phase I and II studies: first in the pre-operative setting, and then as a boost after external beam radiation therapy, as a dose-escalation study, to achieve higher local tumor control. (3) Results: HDREBT is safe and effective in achieving a high tumor regression rate and was well tolerated in a phase II multicenter and two matched-pair studies. (4) Conclusions: HDREBT is a conformed radiation therapy that is safe and effective, and is presently explored in a phase III dose-escalation study in the NOM of patients with operable rectal cancer.
FOXC2 Promotes Vasculogenic Mimicry in Ovarian Cancer
Authors: Recouvreux Maria Sol , Miao Jiangyong , Gozo Maricel C. , Wu Jingni , Walts Ann E. , Karlan Beth Y. , Orsulic Sandra
Published: October 2022

FOXC2 is a forkhead family transcription factor that plays a critical role in specifying mesenchymal cell fate during embryogenesis. FOXC2 expression is associated with increased metastasis and poor survival in various solid malignancies. Using in vitro and in vivo assays in mouse ovarian cancer cell lines, we confirmed the previously reported mechanisms by which FOXC2 could promote cancer growth, metastasis, and drug resistance, including epithelial-mesenchymal transition, stem cell-like differentiation, and resistance to anoikis. In addition, we showed that FOXC2 expression is associated with vasculogenic mimicry in mouse and human ovarian cancers. FOXC2 overexpression increased the ability of human ovarian cancer cells to form vascular-like structures in vitro, while inhibition of FOXC2 had the opposite effect. Thus, we present a novel mechanism by which FOXC2 might contribute to cancer aggressiveness and poor patient survival.
Can Radiomics Provide Additional Information in [18F]FET-Negative Gliomas?
Authors: von Rohr Katharina , Unterrainer Marcus , Holzgreve Adrien , Kirchner Maximilian A. , Li Zhicong , Unterrainer Lena M. , Suchorska Bogdana , Brendel Matthias , Tonn Joerg-Christian , Bartenstein Peter , Ziegler Sibylle , Albert Nathalie L. , Kaiser Lena
Published: October 2022

The purpose of this study was to evaluate the possibility of extracting relevant information from radiomic features even in apparently [18F]FET-negative gliomas. A total of 46 patients with a newly diagnosed, histologically verified glioma that was visually classified as [18F]FET-negative were included. Tumor volumes were defined using routine T2/FLAIR MRI data and applied to extract information from dynamic [18F]FET PET data, i.e., early and late tumor-to-background (TBR5–15, TBR20–40) and time-to-peak (TTP) images. Radiomic features of healthy background were calculated from the tumor volume of interest mirrored in the contralateral hemisphere. The ability to distinguish tumors from healthy tissue was assessed using the Wilcoxon test and logistic regression. A total of 5, 15, and 69% of features derived from TBR20–40, TBR5–15, and TTP images, respectively, were significantly different. A high number of significantly different TTP features was even found in isometabolic gliomas (after exclusion of photopenic gliomas) with visually normal [18F]FET uptake in static images. However, the differences did not reach satisfactory predictability for machine-learning-based identification of tumor tissue. In conclusion, radiomic features derived from dynamic [18F]FET PET data may extract additional information even in [18F]FET-negative gliomas, which should be investigated in larger cohorts and correlated with histological and outcome features in future studies.
Dose-Response Analysis Describes Particularly Rapid Repopulation of Non-Small Cell Lung Cancer during Concurrent Chemoradiotherapy
Authors: Huang Huei-Tyng , Nix Michael G. , Brand Douglas H. , Cobben David , Hiley Crispin T. , Fenwick John D. , Hawkins Maria A.
Published: October 2022

(1) Purpose: We analysed overall survival (OS) rates following radiotherapy (RT) and chemo-RT of locally-advanced non-small cell lung cancer (LA-NSCLC) to investigate whether tumour repopulation varies with treatment-type, and to further characterise the low α/β ratio found in a previous study. (2) Materials and methods: Our dataset comprised 2-year OS rates for 4866 NSCLC patients (90.5% stage IIIA/B) belonging to 51 cohorts treated with definitive RT, sequential chemo-RT (sCRT) or concurrent chemo-RT (cCRT) given in doses-per-fraction ≤3 Gy over 16–60 days. Progressively more detailed dose-response models were fitted, beginning with a probit model, adding chemotherapy effects and survival-limiting toxicity, and allowing tumour repopulation and α/β to vary with treatment-type and stage. Models were fitted using the maximum-likelihood technique, then assessed via the Akaike information criterion and cross-validation. (3) Results: The most detailed model performed best, with repopulation offsetting 1.47 Gy/day (95% confidence interval, CI: 0.36, 2.57 Gy/day) for cCRT but only 0.30 Gy/day (95% CI: 0.18, 0.47 Gy/day) for RT/sCRT. The overall fitted tumour α/β ratio was 3.0 Gy (95% CI: 1.6, 5.6 Gy). (4) Conclusion: The fitted repopulation rates indicate that cCRT schedule durations should be shortened to the minimum in which prescribed doses can be tolerated. The low α/β ratio suggests hypofractionation should be efficacious.
Colorectal Cancer and Purinergic Signalling: An Overview
Authors: Roliano Gabriela , Azambuja Juliana , Brunetto Veronica , Butterfield Hannah , Kalil Antonio , Braganhol Elizandra
Published: October 2022

Colorectal cancer (CRC) is among the most common cancers and exhibits a high fatality rate. Gut inflammation is related to CRC, with loss of homeostasis in immune cell activities. The cells of the innate and adaptive immune system, including macrophages, neutrophils, mast cells, and lymphocytes, are present in most solid tumors. Purinergic signaling allows for communication between immune cells within the tumor microenvironment (TME) and can alter the TME to promote tumor progression. This system is regulated by the availability of extracellular purines to activate purinoceptors (P1 and P2) and is tightly controlled by ectonucleotidases (E-NPP, CD73/CD39, ADA) and kinases, which interact with and modify nucleotides and nucleosides availability. In this review, we compiled articles detailing the relationship of the purinergic system with CRC progression. We found that increased expression of CD73 leads to the suppression of effector immune cell functions and tumor progression in CRC. The P1 family purinoceptors A1, A2A, and A2B were positively associated with tumor progression, but A2B resulted in increased cancer cell apoptosis. The P2 family purinoceptors P2X5, P2X7, P2Y2, P2Y6, and P2Y12 were factors primarily associated with promoting CRC progression. In summary, CD39/CD73 axis and the purinergic receptors exhibit diagnostic and prognostic value and have potential as therapeutic targets in CRC.
Lung Subregion Partitioning by Incremental Dose Intervals Improves Omics-Based Prediction for Acute Radiation Pneumonitis in Non-Small-Cell Lung Cancer Patients
Authors: Li Bing , Zheng Xiaoli , Zhang Jiang , Lam Saikit , Guo Wei , Wang Yunhan , Cui Sunan , Teng Xinzhi , Zhang Yuanpeng , Ma Zongrui , Zhou Ta , Lou Zhaoyang , Meng Lingguang , Ge Hong , Cai Jing
Published: October 2022

Purpose: To evaluate the effectiveness of features obtained from our proposed incremental-dose-interval-based lung subregion segmentation (IDLSS) for predicting grade ≥ 2 acute radiation pneumonitis (ARP) in lung cancer patients upon intensity-modulated radiotherapy (IMRT). (1) Materials and Methods: A total of 126 non-small-cell lung cancer patients treated with IMRT were retrospectively analyzed. Five lung subregions (SRs) were generated by the intersection of the whole lung (WL) and five sub-regions receiving incremental dose intervals. A total of 4610 radiomics features (RF) from pre-treatment planning computed tomographic (CT) and 213 dosiomics features (DF) were extracted. Six feature groups, including WL-RF, WL-DF, SR-RF, SR-DF, and the combined feature sets of WL-RDF and SR-RDF, were generated. Features were selected by using a variance threshold, followed by a Student t-test. Pearson’s correlation test was applied to remove redundant features. Subsequently, Ridge regression was adopted to develop six models for ARP using the six feature groups. Thirty iterations of resampling were implemented to assess overall model performance by using the area under the Receiver-Operating-Characteristic curve (AUC), accuracy, precision, recall, and F1-score. (2) Results: The SR-RDF model achieved the best classification performance and provided significantly better predictability than the WL-RDF model in training cohort (Average AUC: 0.98 ± 0.01 vs. 0.90 ± 0.02, p < 0.001) and testing cohort (Average AUC: 0.88 ± 0.05 vs. 0.80 ± 0.04, p < 0.001). Similarly, predictability of the SR-DF model was significantly stronger than that of the WL-DF model in training cohort (Average AUC: 0.88 ± 0.03 vs. 0.70 ± 0.030, p < 0.001) and in testing cohort (Average AUC: 0.74 ± 0.08 vs. 0.65 ± 0.06, p < 0.001). By contrast, the SR-RF model significantly outperformed the WL-RF model only in the training set (Average AUC: 0.93 ± 0.02 vs. 0.85 ± 0.03, p < 0.001), but not in the testing set (Average AUC: 0.79 ± 0.05 vs. 0.77 ± 0.07, p = 0.13). (3) Conclusions: Our results demonstrated that the IDLSS method improved model performance for classifying ARP with grade ≥ 2 when using dosiomics or combined radiomics-dosiomics features.
Defining A Liquid Biopsy Profile of Circulating Tumor Cells and Oncosomes in Metastatic Colorectal Cancer for Clinical Utility
Authors: Narayan Sachin , Courcoubetis George , Mason Jeremy , Naghdloo Amin , Kolenčík Drahomír , Patterson Scott D. , Kuhn Peter , Shishido Stephanie N.
Published: October 2022

Metastatic colorectal cancer (mCRC) is characterized by its extensive disease heterogeneity, suggesting that individualized analysis could be vital to improving patient outcomes. As a minimally invasive approach, the liquid biopsy has the potential to longitudinally monitor heterogeneous analytes. Current platforms primarily utilize enrichment-based approaches for epithelial-derived circulating tumor cells (CTC), but this subtype is infrequent in the peripheral blood (PB) of mCRC patients, leading to the liquid biopsy’s relative disuse in this cancer type. In this study, we evaluated 18 PB samples from 10 mCRC patients using the unbiased high-definition single-cell assay (HDSCA). We first employed a rare-event (Landscape) immunofluorescence (IF) protocol, which captured a heterogenous CTC and oncosome population, the likes of which was not observed across 50 normal donor (ND) samples. Subsequent analysis was conducted using a colorectal-targeted IF protocol to assess the frequency of CDX2-expressing CTCs and oncosomes. A multi-assay clustering analysis isolated morphologically distinct subtypes across the two IF stains, demonstrating the value of applying an unbiased single-cell approach to multiple assays in tandem. Rare-event enumerations at a single timepoint and the variation of these events over time correlated with progression-free survival. This study supports the clinical utility of an unbiased approach to interrogating the liquid biopsy in mCRC, representing the heterogeneity within the CTC classification and warranting the further molecular characterization of the rare-event analytes with clinical promise.
Prognostic Value of Neutrophil Percentage-to-Albumin Ratio in Patients with Oral Cavity Cancer
Authors: Ko Chien-An , Fang Ku-Hao , Tsai Ming-Shao , Lee Yi-Chan , Lai Chia-Hsuan , Hsu Cheng-Ming , Huang Ethan I. , Chang Geng-He , Tsai Yao-Te
Published: October 2022

This study investigated preoperative neutrophil percentage-to-albumin ratio (NPAR) for predicting oral cavity squamous cell carcinoma (OSCC) survival. We retrospectively analyzed 368 patients who received curative OSCC surgery between 2008 and 2017. Receiver operating characteristic curve analyses were employed to identify the optimal NPAR cutoff (16.93), and the patients were then separated into low-NPAR and high-NPAR groups. Intergroup differences in survival were determined through Kaplan–Meier analysis and log-rank tests. Disease-free survival (DFS) and overall survival (OS) predictors were identified using Cox proportional-hazards models. A nomogram integrating independent prognostic factors was proposed to increase the accuracy of OS prediction. A high NPAR (≥16.93) was associated with worse median OS and DFS than was a low NPAR (both p < 0.001); this finding was confirmed through multivariate analyses (hazard ratio (HR) for OS = 2.697, p < 0.001; and HR for DFS = 1.671, p = 0.008). The nomogram’s favorable predictive ability was confirmed by the calibration plots and concordance index (0.784). The preoperative NPAR is thus a promising prognostic biomarker in patients with OSCC after external validation in a larger cohort. Our nomogram can facilitate clinical use of the NPAR and provides accurate individualized OS predictions.
Identification of Predictive Factors for Overall Survival and Response during Hypomethylating Treatment in Very Elderly (≥75 Years) Acute Myeloid Leukemia Patients: A Multicenter Real-Life Experience
Authors: Molica Matteo , Mazzone Carla , Niscola Pasquale , Carmosino Ida , Di Veroli Ambra , De Gregoris Cinzia , Bonanni Fabrizio , Perrone Salvatore , Cenfra Natalia , Fianchi Luana , Piccioni Anna Lina , Spadea Antonio , Luzi Giovanni , Mengarelli Andrea , Cudillo Laura , Maurillo Luca , Pagano Livio , Breccia Massimo , Rigacci Luigi , De Fabritiis Paolo
Published: October 2022

Elderly patients represent the most challenging and hard-to-treat patient population due to dismal characteristics of the disease, such as secondary-acute myeloid leukemia (AML), enrichment of unfavorable molecular genes (TP53) and comorbidities. We conducted a multicentric retrospective study to evaluate activity and safety in a real-life setting of hypomethylating drugs (HMAs) in patients older than 75 years with AML. Between September 2010 and December 2021, 220 patients were treated, 164 (74.5%) received AZAcitidine and 56 DECitabine; most patients (57.8%), received more than four cycles of HMAs. The best response obtained was CR in 51 patients (23.2%), PR in 23 (10.5%) and SD in 45 (20.5%); overall transfusion independence was obtained in 47 patients (34%), after a median of 3.5 months. The median OS (mOs) was 8 months (95% CI 5.9–10.2), with 1- and 2-years OS of 39.4% (95% CI 32.7–46) and 17.4% (95% CI 11.7–23.1), respectively; similar mOS was observed according to HMA treatment (AZA 8.3 vs. DEC 7.8 months, p = 0.810). A subset of 57 long survivors (44 in AZA group and 13 in DEC group) received at least 12 cycles of HMAs, their mOS was 24.3 months. In multivariate analysis, age (≥80), Charlson comorbidity index (≥3), creatinine clearance and the type of best response (≥PR) during treatment maintained independent significance in predicting survival. Infectious complications, most frequently pneumonia (35) and septic shock (12), were lethal in 49 patients (22.2%). Our data show that HMAs have similar efficacy compared to pivotal trials and are well tolerated in a setting of very elderly patients with several co-comorbidities.
Circulating Cytokines Reflect the Etiology-Specific Immune Environment in Cirrhosis and HCC
Authors: Beudeker Boris J. B. , Groothuismink Zwier M. A. , van der Eijk Annemiek A. , Debes Jose D. , Boonstra Andre
Published: October 2022

Background and Aims: Chronic liver disease—from any etiology—can progress to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The progression of liver cirrhosis to the end stages of disease is influenced by a variety of factors, including inflammatory cytokines. We pursued a study of cytokine-mediated inflammatory responses in hepatitis B (HBV), hepatitis C (HCV), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) patients with liver cirrhosis. Methods: Immune profiles were determined through the serum multiplex profiling of >100 cytokines in a 188 cirrhotic patients, 35 healthy controls and 196 early-stage HCC patients. Results: Patients with liver cirrhosis exhibited a vast upregulation of proinflammatory cytokines (p < 0.0001), including those with pro-oncogenic features, when compared to healthy individuals. In contrast to prevailing assumptions, each etiological cause of cirrhosis exhibited a unique cytokine profile in blood. Regardless of antiviral therapy, HBV cirrhosis patients had the largest number of upregulated proinflammatory mediators, compared to HCV, ALD and NAFLD (p < 0.0001). To further evaluate the etiology-dependent modulation of cytokine response in relation to liver cancer, we studied cytokine profiles in early-stage HCC patients strictly stratified by underlying liver disease. We observed unique sets of differentially expressed cytokines in each cohort of early-stage HCC patients of different cirrhosis etiologies. Conclusions: Our findings, therefore, underscore the importance of stratification by the etiological cause of liver cirrhosis in immune-based studies.
Time Trends in Treatment Strategies and Survival of Older versus Younger Patients with Synchronous Metastasised Melanoma—A Population-Based Study in the Netherlands Cancer Registry
Authors: van der Ziel Daisy , Derks Marloes G. M. , Kapiteijn Ellen , Bastiaannet Esther , Louwman Marieke , van den Bos Frederiek , Mooijaart Simon P. , Portielje Johanneke E. A. , de Glas Nienke A.
Published: October 2022

Around 45% of patients with melanoma are older than 65 years. In recent years, immunotherapy has proven very effective for metastasised melanoma. The aim of this study was to investigate the time trends in treatment strategies and survival in older versus younger patients with synchronous metastasised melanoma. We included all patients diagnosed between 2000 and 2019 from the Netherlands cancer registry. We analysed changes in first-line systemic treatment using multivariable logistic regression models, stratified by age (<65, 65–75, and ≥75). Changes in overall survival were studied using multivariable Cox regression analysis. A total of 2967 patients were included. Immunotherapy prescription increased significantly over time for all age groups (<65 years: 11.8% to 64.9%, p < 0.001; 65–75 years: 0% to 68.6%, p < 0.001; >75 years: 0% to 39.5%, p < 0.001). In multivariable analyses, overall survival improved for patients aged <65 and 65–75 (HR 0.96, 95% CI 0.92–1.00 and HR 0.95, 95% CI 0.89–1.00, respectively), but not in patients over 75 (HR 0.98, 95% CI 0.91–1.05). In conclusion, overall survival has improved in patients with synchronous metastasised melanoma aged <75 years, but not in patients aged 75 years or older. This might be explained by lower prescription rates of immunotherapy in this age group.
The Association between Peptic Ulcer Disease and Gastric Cancer: Results from the Stomach Cancer Pooling (StoP) Project Consortium
Authors: Paragomi Pedram , Dabo Bashir , Pelucchi Claudio , Bonzi Rossella , Bako Abdulaziz T. , Sanusi Nabila Muhammad , Nguyen Quan H. , Zhang Zuo-Feng , Palli Domenico , Ferraroni Monica , Vu Khanh Truong , Yu Guo-Pei , Turati Federica , Zaridze David , Maximovitch Dmitry , Hu Jinfu , Mu Lina , Boccia Stefania , Pastorino Roberta , Tsugane Shoichiro , Hidaka Akihisa , Kurtz Robert C. , Lagiou Areti , Lagiou Pagona , Camargo M. Constanza , Curado Maria Paula , Lunet Nuno , Vioque Jesus , Boffetta Paolo , Negri Eva , La Vecchia Carlo , Luu Hung N.
Published: October 2022

Background. Gastric cancer (GC) is the fifth most common type of cancer and the fourth most common cause of cancer-related mortality. Although the risk of GC and peptic ulcer disease (PUD) is known to be increased by H. pylori infection, evidence regarding the direct relationship between PUD and GC across ethnicities is inconclusive. Therefore, we investigated the association between PUD and GC in the Stomach cancer Pooling (StoP) consortium. Methods. History of peptic ulcer disease was collected using a structured questionnaire in 11 studies in the StoP consortium, including 4106 GC cases and 6922 controls. The two-stage individual-participant data meta-analysis approach was adopted to generate a priori. Unconditional logistic regression and Firth’s penalized maximum likelihood estimator were used to calculate study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between gastric ulcer (GU)/duodenal ulcer (DU) and risk of GC. Results. History of GU and DU was thoroughly reported and used in association analysis, respectively, by 487 cases (12.5%) and 276 controls (4.1%), and 253 cases (7.8%) and 318 controls (6.0%). We found that GU was associated with an increased risk of GC (OR = 3.04, 95% CI: 2.07–4.49). No association between DU and GC risk was observed (OR = 1.03, 95% CI: 0.77–1.39). Conclusions. In the pooled analysis of 11 case–control studies in a large consortium (i.e., the Stomach cancer Pooling (StoP) consortium), we found a positive association between GU and risk of GC and no association between DU and GC risk.
Development of a Clinically Applicable NanoString-Based Gene Expression Classifier for Muscle-Invasive Bladder Cancer Molecular Stratification
Authors: Olkhov-Mitsel Ekaterina , Yu Yanhong , Lajkosz Katherine , Liu Stanley K. , Vesprini Danny , Sherman Christopher G. , Downes Michelle R.
Published: October 2022

Transcriptional profiling of muscle-invasive bladder cancer (MIBC) using RNA sequencing (RNA-seq) technology has demonstrated the existence of intrinsic basal and luminal molecular subtypes that vary in their prognosis and response to therapy. However, routine use of RNA-seq in a clinical setting is restricted by cost and technical difficulties. Herein, we provide a single-sample NanoString-based seven-gene (KRT5, KRT6C, SERPINB13, UPK1A, UPK2, UPK3A and KRT20) MIBC molecular classifier that assigns a luminal and basal molecular subtype. The classifier was developed in a series of 138 chemotherapy naïve MIBCs split into training (70%) and testing (30%) datasets. Further, we validated the previously published CK5/6 and GATA3 immunohistochemical classifier which showed high concordance of 96.9% with the NanoString-based gene expression classifier. Immunohistochemistry-based molecular subtypes significantly correlated with recurrence-free survival (RFS) and disease-specific survival (DSS) in univariable (p  =  0.006 and p  =  0.011, respectively) and multivariate cox regression analysis for DSS (p = 0.032). Used sequentially, the immunohistochemical- and NanoString-based classifiers provide faster turnaround time, lower cost per sample and simpler data analysis for ease of clinical implementation in routine diagnostics.