bluuebunny/crossref_metadata_2025 huggingface dataset:
Easy and Low-Cost Method for Synthesis of Carbon–Silica Composite from Vinasse and Study of Ibuprofen Removal
Authors: Ngernyen Yuvarat , Siriketh Thitipong , Manyuen Kritsada , Thawngen Panta , Rodtoem Wipha , Wannuea Kritiyaporn , Knijnenburg Jesper T. N. , Budsaereechai Supattra
Published: October 2022

Vinasse was successfully utilized to synthesize carbon–silica composite with a low-cost silica source available in Thailand (sodium silicate, Na2SiO3) and most commonly used source, tetraethyl orthosilicate (TEOS). The composites were prepared by a simple one-step sol–gel process by varying the vinasse (as carbon source) to silica source (Na2SiO3 or TEOS) weight ratio. The resulting composites were characterized by N2 adsorption, moisture and ash contents, pH, pHpzc, bulk density, Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and scanning electron microscopy-energy dispersive X-ray analysis (SEM-EDX). The composites had highest surface area of 313 and 456 m2/g, with average mesopore diameters of 5.00 and 2.62 nm when using Na2SiO3 and TEOS as the silica sources, respectively. The adsorption of a non-steroidal anti-inflammatory drug, ibuprofen, was investigated. The contact time to reach equilibrium was 60 min for both composites. The adsorption kinetics were fitted by a pseudo-second-order model with the correlation coefficient R2 > 0.997. The adsorption isotherms were well described by the Langmuir model (R2 > 0.992), which indicates monolayer adsorption. The maximal adsorption capacities of the Na2SiO3- and TEOS-based composites were as high as 406 and 418 mg/g at pH 2, respectively. The research results indicate that vinasse and a low-cost silica source (Na2SiO3) show great potential to synthesize adsorbents through a simple method with high efficiency.
Exploring MicroRNA and Exosome Involvement in Malignant Pleural Mesothelioma Drug Response
Authors: Johnson Ben , Zhuang Ling , Rath Emma M. , Yuen Man Lee , Cheng Ngan Ching , Shi Huaikai , Kao Steven , Reid Glen , Cheng Yuen Yee
Published: October 2022

Malignant pleural mesothelioma (MPM) is a deadly thoracic malignancy and existing treatment options are limited. Chemotherapy remains the most widely used first-line treatment regimen for patients with unresectable MPM, but is hampered by drug resistance issues. The current study demonstrated a modest enhancement of MPM cell sensitivity to chemotherapy drug treatment following microRNA (miRNA) transfection in MPM cell lines, albeit not for all tested miRNAs. This effect was more pronounced for FAK (PND-1186) small molecule inhibitor treatment; consistent with previously published data. We previously established that MPM response to survivin (YM155) small molecule inhibitor treatment is unrelated to basal survivin expression. Here, we showed that MPM response to YM155 treatment is enhanced following miRNA transfection of YM155-resistant MPM cells. We determined that YM155-resistant MPM cells secrete a higher level of exosomes in comparison to YM155-sensitive MPM cells. Despite this, an exosome inhibitor (GW4896) did not enhance MPM cell sensitivity to YM155. Additionally, our study showed no evidence of a correlation between the mRNA expression of inhibitor of apoptosis (IAP) gene family members and MPM cell sensitivity to YM155. However, two drug transporter genes, ABCA6 and ABCA10, were upregulated in the MPM cell lines and correlated with poor sensitivity to YM155.
Impact of COVID-19 on Intracranial Meningioma Resection: Results from California State Inpatient Database
Authors: Rubens Muni , Saxena Anshul , Ramamoorthy Venkataraghavan , Ahmed Md Ashfaq , Zhang Zhenwei , McGranaghan Peter , Veledar Emir , McDermott Michael
Published: October 2022

Purpose: To assess the effects of COVID-19 on hospitalizations for intracranial meningioma resection using a large database. Methods: We conducted a retrospective analysis of the California State Inpatient Database (SID) 2019 and 2020. All adult (18 years or older) hospitalizations were included for the analysis. The primary outcomes were trends in hospitalization for intracranial meningioma resection between 2019 and 2020. Secondary outcomes were Clavien–Dindo grade IV complications, in-hospital mortality, and prolonged length of stay, which was defined as length of stay ≥75 percentile. Results: There were 3,173,333 and 2,866,161 hospitalizations in 2019 and 2020, respectively (relative decrease, 9.7%), of which 921 and 788 underwent intracranial meningioma resection (relative decrease, 14.4%). In 2020, there were 94,114 admissions for COVID-19 treatment. Logistic regression analysis showed that year in which intracranial meningioma resection was performed did not show significant association with Clavien–Dindo grade IV complications and in-hospital mortality (OR, 1.23, 95% CI: 0.78–1.94) and prolonged length of stay (OR, 1.05, 95% CI: 0.84–1.32). Conclusion: Our findings show that neurosurgery practice in the US successfully adapted to the unforeseen challenges posed by COVD-19 and ensured the best quality of care to the patients.
Anoikis-Associated Lung Cancer Metastasis: Mechanisms and Therapies
Authors: Wang Jing , Luo Zhijie , Lin Lizhu , Sui Xinbing , Yu Lili , Xu Cong , Zhang Ruonan , Zhao Ziming , Zhu Qianru , An Bo , Wang Qiao , Chen Bi , Leung Elaine Lai-Han , Wu Qibiao
Published: October 2022

Tumor metastasis occurs in lung cancer, resulting in tumor progression and therapy failure. Anoikis is a mechanism of apoptosis that combats tumor metastasis; it inhibits the escape of tumor cells from the native extracellular matrix to other organs. Deciphering the regulators and mechanisms of anoikis in cancer metastasis is urgently needed to treat lung cancer. Several natural and synthetic products exhibit the pro-anoikis potential in lung cancer cells and in vivo models. These products include artonin E, imperatorin, oroxylin A, lupalbigenin, sulforaphane, renieramycin M, avicequinone B, and carbenoxolone. This review summarizes the current understanding of the molecular mechanisms of anoikis regulation and relevant regulators involved in lung cancer metastasis and discusses the therapeutic potential of targeting anoikis in the treatment of lung cancer metastasis.
Intestinal Microbiota: The Driving Force behind Advances in Cancer Immunotherapy
Authors: Dai Zhujiang , Fu Jihong , Peng Xiang , Tang Dong , Song Jinglue
Published: October 2022

In recent years, cancer immunotherapy has become a breakthrough method to solve solid tumors. It uses immune checkpoint inhibitors to interfere with tumor immune escape to coordinate anti-tumor therapy. However, immunotherapy has an individualized response rate. Moreover, immune-related adverse events and drug resistance are still urgent issues that need to be resolved, which may be attributed to the immune imbalance caused by immune checkpoint inhibitors. Microbiome research has fully revealed the metabolic-immune interaction relationship between the microbiome and the host. Surprisingly, sequencing technology further proved that intestinal microbiota could effectively intervene in tumor immunotherapy and reduce the incidence of adverse events. Therefore, cancer immunotherapy under the intervention of intestinal microbiota has innovatively broadened the anti-tumor landscape and is expected to become an active strategy to enhance individualized responses.
CREPT Disarms the Inhibitory Activity of HDAC1 on Oncogene Expression to Promote Tumorigenesis
Authors: Cao Yajun , Ning Bobin , Tian Ye , Lan Tingwei , Chu Yunxiang , Ren Fangli , Wang Yinyin , Meng Qingyu , Li Jun , Jia Baoqing , Chang Zhijie
Published: October 2022

Histone deacetylases 1 (HDAC1), an enzyme that functions to remove acetyl molecules from ε-NH3 groups of lysine in histones, eliminates the histone acetylation at the promoter regions of tumor suppressor genes to block their expression during tumorigenesis. However, it remains unclear why HDAC1 fails to impair oncogene expression. Here we report that HDAC1 is unable to occupy at the promoters of oncogenes but maintains its occupancy with the tumor suppressors due to its interaction with CREPT (cell cycle-related and expression-elevated protein in tumor, also named RPRD1B), an oncoprotein highly expressed in tumors. We observed that CREPT competed with HDAC1 for binding to oncogene (such as CCND1, CLDN1, VEGFA, PPARD and BMP4) promoters but not the tumor suppressor gene (such as p21 and p27) promoters by a chromatin immunoprecipitation (ChIP) qPCR experiment. Using immunoprecipitation experiments, we deciphered that CREPT specifically occupied at the oncogene promoter via TCF4, a transcription factor activated by Wnt signaling. In addition, we performed a real-time quantitative PCR (qRT-PCR) analysis on cells that stably over-expressed CREPT and/or HDAC1, and we propose that HDAC1 inhibits CREPT to activate oncogene expression under Wnt signaling activation. Our findings revealed that HDAC1 functions differentially on tumor suppressors and oncogenes due to its interaction with the oncoprotein CREPT.
ERCC1 Overexpression Increases Radioresistance in Colorectal Cancer Cells
Authors: Huang Yi-Jung , Huang Ming-Yii , Cheng Tian-Lu , Kuo Shih-Hsun , Ke Chien-Chih , Chen Yi-Ting , Hsieh Yuan-Chin , Wang Jaw-Yuan , Cheng Chiu-Min , Chuang Chih-Hung
Published: October 2022

Preoperative concurrent chemoradiotherapy (CCRT) is a standard treatment for locally advanced rectal cancer patients, but 20–30% do not benefit from the desired therapeutic effects. Previous reports indicate that high levels of ERCC1 reduce the effectiveness of cisplatin-based CCRT; however, it remains unclear as to whether ERCC1 overexpression increases radiation resistance. To clarify the correlation between ERCC1 levels and radiation (RT) resistance, we established two cell lines (HCT116-Tet-on and COLO205-Tet-on), induced them to overexpress ERCC1, detected cell survival following exposure to radiation, established HCT116-Tet-on and COLO205-Tet-on heterotopic cancer animal models, and detected tumor volume following exposure to radiation. We found that ERCC1 overexpression increased radiation resistance. After regulating ERCC1 levels and radiation exposure to verify the correlation, we noted that increased radiation resistance was dependent on ERCC1 upregulation in both cell lines. For further verification, we exposed HCT116-Tet-on and COLO205-Tet-on heterotopic cancer animal models to radiation and observed that ERCC1 overexpression increased colorectal cancer tumor radioresistance in both. Combined, our results suggest that ERCC1 overexpression may serve as a suitable CCRT prognostic marker for colorectal cancer patients.
Significant Rise of Colorectal Cancer Incidence in Younger Adults and Strong Determinants: 30 Years Longitudinal Differences between under and over 50s
Authors: Sifaki-Pistolla Dimitra , Poimenaki Viktoria , Fotopoulou Ilektra , Saloustros Emmanouil , Mavroudis Dimitrios , Vamvakas Lampros , Lionis Christos
Published: October 2022

(1) Background: There is evidence in the recent literature that the incidence patterns of colorectal cancer (CRC) have changed considerably over the years, tending to rise rapidly in individuals under 50 years old compared with those over 50 years. The current study aimed to assess the incidence of CRC in Crete from 1992–2021 and compare them among younger and older adults. (2) Methods: Data on malignant neoplasms of colon, rectosigmoid junction, and rectum have been extracted from the database of the Regional Cancer Registry of Crete. (3) Results: The number of these cases for the period 1992–2021 was 3857 (n = 2895 colon and n = 962 rectum). The mean age-specific incidence rate (ASpIR/100,000/year) of colon cancer patients <50 years was 7.2 (95% CI 5.1–9.7), while for patients ≥50 years the ASpIR was 149 (95% CI 146.2–153.4). ASpIR presented a 29.6% increase from 2001 to 2011 in the age group of 20–34 years and further increase is expected from 2022–2030 (projected change, 42.8%). The main risk factors were the pack years (p = 0.01), alcohol consumption (0.02), and farmer occupation (0.04), especially during 2012–2021. (4) Conclusions: We confirmed an increased incidence of CRC in young adults <50 in a European population with low cancer incidence in the past and a worrisome prediction for the near future. The observed trends clearly indicate that starting CRC screening at an earlier age may be essential.
Heterogeneity and Functions of Tumor-Infiltrating Antibody Secreting Cells: Lessons from Breast, Ovarian, and Other Solid Cancers
Authors: Lounici Yasmine , Le Saux Olivia , Chemin Gabriel , Wajda Pauline , Barrin Sarah , Berthet Justine , Caux Christophe , Dubois Bertrand
Published: October 2022

Neglected for a long time in cancer, B cells and ASCs have recently emerged as critical actors in the tumor microenvironment, with important roles in shaping the antitumor immune response. ASCs indeed exert a major influence on tumor growth, patient survival, and response to therapies. The mechanisms underlying their pro- vs. anti-tumor roles are beginning to be elucidated, revealing the contributions of their secreted antibodies as well as of their emerging noncanonical functions. Here, concentrating mostly on ovarian and breast cancers, we summarize the current knowledge on the heterogeneity of tumor-infiltrating ASCs, we discuss their possible local or systemic origin in relation to their immunoglobulin repertoire, and we review the different mechanisms by which antibody (Ab) subclasses and isoforms differentially impact tumor cells and anti-tumor immunity. We also discuss the emerging roles of cytokines and other immune modulators produced by ASCs in cancer. Finally, we propose strategies to manipulate the tumor ASC compartment to improve cancer therapies.
Preclinical Efficacy and Toxicology Evaluation of RAC1 Inhibitor 1A-116 in Human Glioblastoma Models
Authors: Cardama Georgina A. , Maggio Julian , Valdez Capuccino Lucas , Gonzalez Nazareno , Matiller Valentina , Ortega Hugo H. , Perez German R. , Demarco Ignacio A. , Spitzer Eduardo , Gomez Daniel E. , Lorenzano Menna Pablo , Alonso Daniel F.
Published: October 2022

Malignant gliomas are the most common primary central nervous system tumor in adults. Despite current therapeutics, these tumors are associated with poor prognosis and a median survival of 16 to 19 months. This highlights the need for innovative treatments for this incurable disease. Rac1 has long been associated with tumor progression and plays a key role in glioma’s infiltrative and invasive nature. The aim of this study is to evaluate the 1A-116 molecule, a Rac1 inhibitor, as targeted therapy for this aggressive disease. We found that targeting Rac1 inhibits cell proliferation and cell cycle progression using different in vitro human glioblastoma models. Additionally, we evaluated 1A-116 in vivo, showing a favorable toxicological profile. Using in silico tools, 1A-116 is also predicted to penetrate the blood–brain barrier and present a favorable metabolic fate. In line with these results, 1A-116 i.p daily treatment resulted in a dose-dependent antitumor effect in an orthotopic IDH-wt glioma model. Altogether, our study provides a strong potential for clinical translation of 1A-116 as a signal transduction-based precision therapy for glioma and also increases the evidence of Rac1 as a key molecular target.
Differences and Similarities in the Pattern of Early Metabolic and Morphologic Response after Induction Chemo-Immunotherapy versus Induction Chemotherapy Alone in Locally Advanced Squamous Cell Head and Neck Cancer
Authors: Beck Michael , Semrau Sabine , Haderlein Marlen , Gostian Antoniu-Oreste , Hartwich Julius , Müller Sarina , Kallies Annett , Geppert Carol-Immanuel , Schonath Miriam , Putz Florian , Gaipl Udo , Frey Benjamin , Saake Marc , Iro Heinrich , Uder Michael , Hartmann Arndt , Kuwert Torsten , Fietkau Rainer , Eckstein Markus , Hecht Markus
Published: October 2022

Background: In head and neck cancer patients, parameters of metabolic and morphologic response of the tumor to single-cycle induction chemotherapy (IC) with docetaxel, cis- or carboplatin are used to decide the further course of treatment. This study investigated the effect of adding a double immune checkpoint blockade (DICB) of tremelimumab and durvalumab to IC on imaging parameters and their significance with regard to tumor cell remission. Methods: Response variables of 53 patients treated with IC+DICB (ICIT) were compared with those of 104 who received IC alone. Three weeks after one cycle, pathologic and, in some cases, clinical and endoscopic primary tumor responses were evaluated and correlated with a change in 18F-FDG PET and CT/MRI-based maximum-standardized uptake values (SUVmax) before (SUVmaxpre), after treatment (SUVmaxpost) and residually (resSUVmax in % of SUVmaxpre), and in maximum tumor diameter (Dmax) before (Dmaxpre) and after treatment (Dmaxpost) and residually (resD). Results: Reduction of SUVmax and Dmax occurred in both groups; values were SUVmaxpre: 14.4, SUVmaxpost: 6.6, Dmaxpre: 30 mm and Dmaxpost: 23 mm for ICIT versus SUVmaxpre: 16.5, SUVmaxpost: 6.4, Dmaxpre: 21 mm, and Dmaxpost: 16 mm for IC alone (all p < 0.05). ResSUVmax was the best predictor of complete response (IC: AUC: 0.77; ICIT: AUC: 0.76). Metabolic responders with resSUVmax ≤ 40% tended to have a higher rate of CR to ICIT (88%; n = 15/17) than to IC (65%; n = 30/46; p = 0.11). Of the metabolic nonresponders (resSUVmax > 80%), 33% (n = 5/15) achieved a clinical CR to ICIT versus 6% (n = 1/15) to IC (p = 0.01). Conclusions: ICIT and IC quickly induce a response and 18F-FDG PET is the more accurate modality for identifying complete remission. The rate of discrepant response, i.e., pCR with metabolic nonresponse after ICIT was >30%.
Novel Methods of Targeting IL-1 Signalling for the Treatment of Breast Cancer Bone Metastasis
Authors: Zhou Jiabao , Down Jennifer M. , George Christopher N. , Murphy Jessica , Lefley Diane V. , Tulotta Claudia , Alsharif Marwa A. , Leach Michael , Ottewell Penelope D.
Published: October 2022

Breast cancer bone metastasis is currently incurable. Evidence suggests that inhibiting IL-1 signalling with the IL1R antagonist, Anakinra, or the IL1β antibody, Canakinumab, prevents metastasis and almost eliminates breast cancer growth in the bone. However, these drugs increase primary tumour growth. We, therefore, investigated whether targeting other members of the IL-1 pathway (Caspase-1, IL1β or IRAK1) could reduce bone metastases without increasing tumour growth outside of the bone. Inhibition of IL-1 via MLX01 (IL1β secretion inhibitor), VRT043198/VX765 (Caspase-1 inhibitor), Pacritinib (IRAK1 inhibitor) or Anakinra (IL1R antagonist) on tumour cell viability, migration and invasion were assessed in mouse mammary E0771 and Py8119 cells in vitro and on primary tumour growth, spontaneous metastasis and metastatic outgrowth in vivo. In vitro, Inhibition of IL-1 signalling by MLX01, VRT043198 and Anakinra reduced migration of E0771 and Py8119 cells and reversed tumour-derived IL1β induced-increased invasion and migration towards bone cells. In vivo, VX765 and Anakinra significantly reduced spontaneous metastasis and metastatic outgrowth in the bone, whereas MLX01 reduced primary tumour growth and bone metastasis. Pacritinib had no effect on metastasis in vitro or in vivo. Targeting IL-1 signalling with small molecule inhibitors may provide a new therapeutic strategy for breast cancer bone metastasis.
Nerve Density and Neuronal Biomarkers in Cancer
Authors: Ali Shahrukh R. , Jordan Madeleine , Nagarajan Priyadharsini , Amit Moran
Published: October 2022

Certain histologic characteristics of neurons, novel neuronal biomarkers, and nerve density are emerging as important diagnostic and prognostic tools in several cancers. The tumor microenvironment has long been known to promote tumor development via promoting angiogenesis and cellular proliferation, but new evidence has shown that neural proliferation and invasion in the tumor microenvironment may also enable tumor growth. Specific neuronal components in peripheral nerves and their localization in certain tumor sites have been identified and associated with tumor aggressiveness. In addition, dense neural innervation has been shown to promote tumorigenesis. In this review, we will summarize the histological components of a nerve, explore the neuronal biomarkers found in tumor sites, and discuss clinical correlates between tumor neurobiology and patient prognosis.
Relevance of Abnormal KCNN1 Expression and Osmotic Hypersensitivity in Ewing Sarcoma
Authors: Fuest Sebastian , Post Christoph , Balbach Sebastian T. , Jabar Susanne , Neumann Ilka , Schimmelpfennig Sandra , Sargin Sarah , Nass Elke , Budde Thomas , Kailayangiri Sareetha , Altvater Bianca , Ranft Andreas , Hartmann Wolfgang , Dirksen Uta , Rössig Claudia , Schwab Albrecht , Pethő Zoltán
Published: October 2022

Ewing sarcoma (EwS) is a rare and highly malignant bone tumor occurring mainly in childhood and adolescence. Physiologically, the bone is a central hub for Ca2+ homeostasis, which is severely disturbed by osteolytic processes in EwS. Therefore, we aimed to investigate how ion transport proteins involved in Ca2+ homeostasis affect EwS pathophysiology. We characterized the expression of 22 candidate genes of Ca2+-permeable or Ca2+-regulated ion channels in three EwS cell lines and found the Ca2+-activated K+ channel KCa2.1 (KCNN1) to be exceptionally highly expressed. We revealed that KCNN1 expression is directly regulated by the disease-driving oncoprotein EWSR1-FL1. Due to its consistent overexpression in EwS, KCNN1 mRNA could be a prognostic marker in EwS. In a large cohort of EwS patients, however, KCNN1 mRNA quantity does not correlate with clinical parameters. Several functional studies including patch clamp electrophysiology revealed no evidence for KCa2.1 function in EwS cells. Thus, elevated KCNN1 expression is not translated to KCa2.1 channel activity in EwS cells. However, we found that the low K+ conductance of EwS cells renders them susceptible to hypoosmotic solutions. The absence of a relevant K+ conductance in EwS thereby provides an opportunity for hypoosmotic therapy that can be exploited during tumor surgery.
Impact of the Coronavirus Disease 2019 (COVID-19) Pandemic on Cervical Cancer Screening in Gynecological Practices in Germany
Authors: Gremke Niklas , Griewing Sebastian , Felgentreff Markus , Kostev Karel , Kalder Matthias
Published: October 2022

Purpose: the aim of this cross-sectional study was to analyze the impact of the COVID-19 pandemic on Cervical Cancer Screening (CCS) in gynecological practices in Germany. Methods: The basis of the analysis was the Uniform Evaluation Standard (EBM) of the Statutory Health Insurance Scheme. This cross-sectional study included all women aged ≥20 years with at least one CCS (clinical and cytological examination) in 223 gynecological practices in Germany during the period 2018–2021. The number of patients with CCS per practice was shown for each year. The average number of patients per year was compared between the pre-pandemic time period (2018, 2019) and the pandemic time period (2020, 2021) using Wilcoxon tests. Analyses were conducted separately for clinical investigations and cytological investigations and were also stratified by age group (20–34, 35–50, >50 years). Results: CCS in gynecological practices significantly decreased in Germany between the pre-pandemic time period of 2018–2019 and the pandemic years of 2020–2021. This decrease was observed in all age groups but was stronger in women aged 20–34 (−25.6%) and weaker in women aged >50 (−15.2%). Conclusions: We found a statistically and clinically relevant decrease of patients receiving CCS in gynecological practices in Germany. This finding is even more exceptional because the new screening algorithm with direct invitations for each patient started in 2020 and was supposed to lead to a higher number of patients in its first years. However, the observed decline in the detection of cervical precancer lesions may lead to increased cervical cancer burden. Risk-based screening strategies and further measures are necessary to adapt to the ongoing COVID-19 pandemic and return to pre-pandemic CCS numbers.
A Novel Selective Axl/Mer/CSF1R Kinase Inhibitor as a Cancer Immunotherapeutic Agent Targeting Both Immune and Tumor Cells in the Tumor Microenvironment
Authors: Jeon Yeejin , Kang Hwankyu , Yang Yeongin , Park Dongsik , Choi Baejung , Kim Jeongjun , Kim Jaeseung , Nam Kiyean
Published: October 2022

Although immune checkpoint blockade (ICB) represents a major breakthrough in cancer immunotherapy, only a limited number of patients with cancer benefit from ICB-based immunotherapy because most immune checkpoint inhibitors (ICIs) target only T cell activation. Therefore, targeting non-T cell components in the tumor microenvironment (TME) can help subvert resistance and increase the applications of ICB-based therapy. Axl and Mer are involved in the carcinogenesis of multiple types of cancer by modulating immune and biological behaviors within tumors. Colony stimulating factor 1 receptor (CSF1R) mediates tumorigenesis in the TME by enhancing tumor associated macrophage (TAM) and myeloid-derived suppressor cell (MDSC) infiltration, facilitating immune escape. Therefore, the simultaneous inhibition of Axl, Mer, and CSF1R kinases may improve therapeutic efficacy by targeting non-T cell components in the TME. Here, we present Q702, a selective, potent small molecule inhibitor targeting Axl, Mer, and CSF1R, for oral administration. Q702 induced antitumor activity in syngeneic tumor mouse models by: remodeling the TME toward immune stimulation; expanding M1 macrophage and CD8 T cell populations and decreasing M2 macrophage and MDSC populations in the TME; and increasing MHC class I and E-cadherin expression in tumor cells. Thus, Q702 may have great potential to broaden the coverage of populations benefiting from ICB-based immunotherapy.
Development of a Prognostic Model of Overall Survival for Metastatic Hormone-Naïve Prostate Cancer in Japanese Men
Authors: Nakagawa Ryunosuke , Iwamoto Hiroaki , Makino Tomoyuki , Naito Renato , Kadomoto Suguru , Akatani Norihito , Yaegashi Hiroshi , Kawaguchi Shohei , Nohara Takahiro , Shigehara Kazuyoshi , Izumi Kouji , Kadono Yoshifumi , Takamatsu Atsushi , Yoshida Kotaro , Mizokami Atsushi
Published: October 2022

Background: Treatment strategies have changed dramatically in recent years with the development of a variety of agents for metastatic hormone-naïve prostate cancer (mHNPC). There is a need to identify prognostic factors for the appropriate choice of treatment for patients with mHNPC, and we retrospectively examined these factors. Methods: Patients with mHNPC treated at our institution from 2000 to 2019 were included in this study. Overall survival (OS) was estimated retrospectively using the Kaplan–Meier method, and factors associated with OS were identified using univariate and multivariate analyses. A prognostic model was then developed based on the factors identified. Follow-up was terminated on 24 October 2021. Results: The median follow-up duration was 44.2 months, whereas the median OS was 85.2 months, with 88 patients succumbing to their disease. Multivariate analysis identified Gleason pattern (GP) 5 content, bone scan index (BSI) ≥ 1.5, and lactate dehydrogenase (LDH) levels ≥ 300 IU/L as prognostic factors associated with OS. We also developed a prognostic model that classified patients with mHNPC as low risk with no factor, intermediate risk with one factor, and high risk with two or three factors. Conclusions: Three prognostic factors for OS were identified in patients with mHNPC, namely GP5 inclusion, BSI ≥ 1.5, and LDH ≥ 300. Using these three factors, we developed a new prognostic model for OS that can more objectively predict patient prognosis.
Ultrasound Radiomics Nomogram to Diagnose Sub-Centimeter Thyroid Nodules Based on ACR TI-RADS
Authors: Lu Wenwu , Zhang Di , Zhang Yuzhi , Qian Xiaoqin , Qian Cheng , Wei Yan , Xia Zicong , Ding Wenbo , Ni Xuejun
Published: October 2022

The aim of the present study was to develop a radiomics nomogram to assess whether thyroid nodules (TNs) < 1 cm are benign or malignant. From March 2021 to March 2022, 156 patients were admitted to the Affiliated Hospital of Nantong University, and from September 2017 to March 2022, 116 patients were retrospectively collected from the Jiangsu Provincial Hospital of Integrated Traditional Chinese and Western Medicine. These patients were divided into a training group and an external test group. A radiomics nomogram was established using multivariate logistics regression analysis using the radiomics score and clinical data, including the ultrasound feature scoring terms from the thyroid imaging reporting and data system (TI-RADS). The radiomics nomogram incorporated the correlated predictors, and compared with the clinical model (training set AUC: 0.795; test set AUC: 0.783) and radiomics model (training set AUC: 0.774; test set AUC: 0.740), had better discrimination performance and correction effects in both the training set (AUC: 0.866) and the test set (AUC: 0.866). Both the decision curve analysis and clinical impact curve showed that the nomogram had a high clinical application value. The nomogram constructed based on TI-RADS and radiomics features had good results in predicting and distinguishing benign and malignant TNs < 1 cm.
Association of CD206 Protein Expression with Immune Infiltration and Prognosis in Patients with Triple-Negative Breast Cancer
Authors: Bobrie Angélique , Massol Océane , Ramos Jeanne , Mollevi Caroline , Lopez-Crapez Evelyne , Bonnefoy Nathalie , Boissière-Michot Florence , Jacot William
Published: October 2022

Background: Triple-negative breast cancers (TNBCs) have a worse prognosis, but might respond to immunotherapies. Macrophages are plastic cells that can adopt various phenotypes and functions. Although they are a major immune population in TNBCs, the relationship between tumor-associated macrophages (TAMs) and TNBC progression has been rarely explored, with controversial results. Methods: We evaluated the prognostic impact of TAMs, quantified by immunohistochemistry with anti-CD68, -IRF8, -CD163, and -CD206 antibodies, in a well-described cohort of 285 patients with non-metastatic TNBC. Results: CD68 (p = 0.008), IRF8 (p = 0.001), and CD163 (p < 0.001) expression positively correlated with higher tumor grade, while CD206 was associated with smaller tumor size (p < 0.001). All macrophage markers were associated with higher tumor-infiltrating lymphocyte numbers and PD-L1 expression. Univariate survival analyses reported a significant positive correlation between CD163+ or CD206+ TAMs and relapse-free survival (respectively: HR = 0.52 [0.28–0.97], p = 0.027, and HR = 0.51 [0.31–0.82], p = 0.005), and between CD206+ TAMs and overall survival (HR = 0.54 [0.35–0.83], p = 0.005). In multivariate analysis, there was a trend for an association between CD206+ TAMs and relapse-free survival (HR = 0.63 [0.33–1.04], p = 0.073). Conclusions: These data suggest that CD206 expression defines a TAM subpopulation potentially associated with favorable outcomes in patients with TNBC. CD206 expression might identify an immune TNBC subgroup with specific therapeutic options.
Practical Implications of KRAS Mutation Status and Sidedness of Primary Tumour in Patients with Colorectal Cancer and Synchronous Liver Metastases: A Subset Analysis of the CoSMIC Study
Authors: Chan Anthony K. C. , Siriwardena Ajith K.
Published: October 2022

Patients with colorectal cancer presenting with synchronous liver metastases have less favourable outcomes than those with primary-only disease. There is evidence of different genetic mutational signatures according to the sidedness of the primary tumour. KRAS mutations are key driver mutations in colorectal cancer progression. This post hoc analysis of the previously reported CoSMIC inception cohort explores the association between primary tumour sidedness and KRAS mutational status on the outcome of patients with colorectal cancer and synchronous liver metastases. Patients diagnosed with synchronous disease were recruited between April 2014 and March 2017 and, after exclusions, 83 patients undergoing colorectal primary KRAS mutation testing constituted the final study population. Data were collected prospectively on demographic profiles, treatment, and outcomes. Twenty-one patients (25%) had right-sided tumours and 62 (75%) had left-sided tumours, with 46 (55%) and 37 (45%) exhibiting wildtype and mutated KRAS, respectively. There was no difference in distribution of liver metastases by KRAS status (unilobar vs. bi-lobar; p = 0.58; Fisher’s Exact test) and no difference in 5-year survival according to KRAS mutation status (Log-rank test, p = 0.82) or tumour sidedness (p = 0.16). In summary, in this cohort of patients with colorectal cancer and synchronous liver metastases, neither KRAS mutation status nor tumour sidedness influenced survival.
Use of Personalized Biomarkers in Metastatic Colorectal Cancer and the Impact of AI
Authors: Volovat Simona-Ruxandra , Augustin Iolanda , Zob Daniela , Boboc Diana , Amurariti Florin , Volovat Constantin , Stefanescu Cipriana , Stolniceanu Cati Raluca , Ciocoiu Manuela , Dumitras Eduard Alexandru , Danciu Mihai , Apostol Delia Gabriela Ciobanu , Drug Vasile , Shurbaji Sinziana Al , Coca Lucia-Georgiana , Leon Florin , Iftene Adrian , Herghelegiu Paul-Corneliu
Published: October 2022

Colorectal cancer is a major cause of cancer-related death worldwide and is correlated with genetic and epigenetic alterations in the colonic epithelium. Genetic changes play a major role in the pathophysiology of colorectal cancer through the development of gene mutations, but recent research has shown an important role for epigenetic alterations. In this review, we try to describe the current knowledge about epigenetic alterations, including DNA methylation and histone modifications, as well as the role of non-coding RNAs as epigenetic regulators and the prognostic and predictive biomarkers in metastatic colorectal disease that can allow increases in the effectiveness of treatments. Additionally, the intestinal microbiota’s composition can be an important biomarker for the response to strategies based on the immunotherapy of CRC. The identification of biomarkers in mCRC can be enhanced by developing artificial intelligence programs. We present the actual models that implement AI technology as a bridge connecting ncRNAs with tumors and conducted some experiments to improve the quality of the model used as well as the speed of the model that provides answers to users. In order to carry out this task, we implemented six algorithms: the naive Bayes classifier, the random forest classifier, the decision tree classifier, gradient boosted trees, logistic regression and SVM.
The Impact of the Hippo Pathway and Cell Metabolism on Pathological Complete Response in Locally Advanced Her2+ Breast Cancer: The TRISKELE Multicenter Prospective Study
Authors: Krasniqi Eriseld , Di Lisa Francesca Sofia , Di Benedetto Anna , Barba Maddalena , Pizzuti Laura , Filomeno Lorena , Ercolani Cristiana , Tinari Nicola , Grassadonia Antonino , Santini Daniele , Minelli Mauro , Montemurro Filippo , Fabbri Maria Agnese , Mazzotta Marco , Gamucci Teresa , D’Auria Giuliana , Botti Claudio , Pelle Fabio , Cavicchi Flavia , Cappelli Sonia , Cappuzzo Federico , Sanguineti Giuseppe , Tomao Silverio , Botticelli Andrea , Marchetti Paolo , Maugeri-Saccà Marcello , De Maria Ruggero , Ciliberto Gennaro , Sperati Francesca , Vici Patrizia
Published: October 2022

The Hippo pathway and its two key effectors, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), are consistently altered in breast cancer. Pivotal regulators of cell metabolism such as the AMP-activated protein kinase (AMPK), Stearoyl-CoA-desaturase 1 (SCD1), and HMG-CoA reductase (HMGCR) are relevant modulators of TAZ/YAP activity. In this prospective study, we measured the tumor expression of TAZ, YAP, AMPK, SCD1, and HMGCR by immunohistochemistry in 65 Her2+ breast cancer patients who underwent trastuzumab-based neoadjuvant treatment. The aim of the study was to assess the impact of the immunohistochemical expression of the Hippo pathway transducers and cell metabolism regulators on pathological complete response. Low expression of cytoplasmic TAZ, both alone and in the context of a composite signature identified by machine learning including also low nuclear levels of YAP and HMGCR and high cytoplasmic levels of SCD1, was a predictor of residual disease in the univariate logistic regression. This finding was not confirmed in the multivariate model including estrogen receptor > 70% and body mass index > 20. However, our findings were concordant with overall survival data from the TCGA cohort. Our results, possibly affected by the relatively small sample size of this study population, deserve further investigation in adequately sized, ad hoc prospective studies.
68Ga-PSMA-11 PET/CT Features Extracted from Different Radiomic Zones Predict Response to Androgen Deprivation Therapy in Patients with Advanced Prostate Cancer
Authors: Tran Vuong Thuy , Tu Shu-Ju , Tseng Jing-Ren
Published: October 2022

Purpose: Prediction of treatment response to androgen deprivation therapy (ADT) prior to treatment initiation remains difficult. This study was undertaken to investigate whether 68Ga-PSMA-11 PET/CT features extracted from different radiomic zones within the prostate gland might predict response to ADT in patients with advanced prostate cancer (PCa). Methods: A total of 35 patients with prostate adenocarcinoma underwent two 68Ga-PSMA-11 PET/CT scans—termed PET-1 and PET-2—before and after 3 months of ADT, respectively. The prostate was divided into three radiomic zones, with zone-1 being the metabolic tumor zone, zone-2 the proximal peripheral tumor zone, and zone-3 the extended peripheral tumor zone. Patients in the response group were those who showed a reduction ratio > 30% for PET-derived parameters measured at PET-1 and PET-2. The remaining patients were classified as non-responders. Results: Seven features (glcm_idmn, glcm_idn, glcm_imc1, ngtdm_Contrast, glrlm_rln, gldm_dn, and shape_MeshVolume) from zone-1, two features (gldm_sdlgle and shape_MinorAxisLength) from zone-2, and two features (diagnostics_Mask-interpolated_Minimum and shape_Sphericity) from zone-3 successfully distinguished responders from non-responders to ADT. One predictive feature (shape_SurfaceVolumeRatio) was consistently identified in all of the three zones. Conclusions: this study demonstrates the potential usefulness of radiomic features extracted from different prostatic zones in distinguishing responders from non-responders prior to ADT initiation.
The Immunocytokine FAP-IL-2v Enhances Anti-Neuroblastoma Efficacy of the Anti-GD2 Antibody Dinutuximab Beta
Authors: Siebert Nikolai , Leopold Justus , Zumpe Maxi , Troschke-Meurer Sascha , Biskupski Simon , Zikoridse Alexander , Lode Holger N.
Published: October 2022

Treatment of high-risk neuroblastoma (NB) patients with the anti-GD2 antibody (Ab) dinutuximab beta (DB) improves survival by 15%. Ab-dependent cellular cytotoxicity (ADCC) is the major mechanism of action and is primarily mediated by NK cells. Since IL-2 co-treatment did not show a therapeutic benefit but strongly induced Treg, we investigated here a DB-based immunotherapy combined with the immunocytokine FAP-IL-2v, which comprises a fibroblast activation protein α (FAP)-specific Ab linked to a mutated IL-2 variant (IL-2v) with abolished binding to the high-affinity IL-2 receptor, thus stimulating NK cells without induction of Treg. Effects of FAP-IL-2v on NK cells, Treg and ADCC mediated by DB, as well as FAP expression in NB, were investigated by flow cytometry, calcein-AM-based cytotoxicity assay and RT-PCR analysis. Moreover, the impact of soluble factors released from tumor cells on FAP expression by primary fibroblasts was assessed. Finally, a combined immunotherapy with DB and FAP-IL-2v was evaluated using a resistant syngeneic murine NB model. Incubation of leukocytes with FAP-IL-2v enhanced DB-specific ADCC without induction of Treg. FAP expression on NB cells and myeloid-derived suppressor cells (MDCS) in tumor tissue was identified. A tumor-cell-dependent enhancement in FAP expression by primary fibroblasts was demonstrated. Combination with DB and FAP-IL-2v resulted in reduced tumor growth and improved survival. Analysis of tumor tissue revealed increased NK and cytotoxic T cell numbers and reduced Treg compared to controls. Our data show that FAP-IL-2v is a potent immunocytokine that augments the efficacy of DB against NB, providing a promising alternative to IL-2.
Emerging Targets in Clear Cell Renal Cell Carcinoma
Authors: Chen Yu-Wei , Rini Brian I. , Beckermann Kathryn E.
Published: October 2022

The dual immune checkpoint blockade targeting CTLA-4 and PD-1 (ipilimumab/nivolumab) or the IO combinations targeting PD-1 and anti-VEGF TKIs (pembrolizumab/axitinib, nivolumab/cabozantinib, pembrolizumab/lenvatinib) have demonstrated an overall survival benefit in advanced clear cell renal cell carcinoma (ccRCC). Despite this significant improvement in clinical outcomes in the frontline setting from IO/IO or the IO/TKI combinations, there is a subset of patients of advanced ccRCC that do not respond to such combinations or will lose the initial efficacy and have disease progression. Therefore, a remarkable unmet need exists to develop new therapeutics to improve outcomes. With an enhanced understanding of ccRCC biology and its interaction with the tumor microenvironment, several new therapies are under development targeting ccRCC metabolism, cytokine-signaling, alternative immune checkpoint proteins, and novel biological pathways. In addition, microbiome products enhancing IO response, antibody–drug conjugates, and targeted radionuclides are also being investigated. This review summarizes selected emerging agents that are under development in ccRCC.
Regulation of TGF-β1-Induced EMT by Autophagy-Dependent Energy Metabolism in Cancer Cells
Authors: Hwang Jin Seok , Lai Trang Huyen , Ahmed Mahmoud , Pham Trang Minh , Elashkar Omar , Bahar Entaz , Kim Deok Ryong
Published: October 2022

Metastasis is associated with poor prognosis and is the major cause of death in cancer patients. The epithelial to mesenchymal transition (EMT) is essential for cancer cells to acquire a highly migratory phenotype. Metabolic reprogramming is required to meet the energy demands during this process. Recent studies have indicated that autophagy is involved in EMT, during which cancer cells depend on autophagy activation for survival. However, accumulating evidence indicates that autophagy’s involvement in cancer is context-dependent, acting as either promoter or inhibitor. In this study, we investigated the role of autophagy in supplying energy to support EMT. We induced EMT in Non-small cell lung cancer A549 cells using TGF-β1 with and without autophagy inhibition. Suppression of autophagy activity by knocking down of BECN1 or chloroquine (CQ) treatment inhibited mesenchymal protein expression. Interestingly, TGF-β1 promoted the transcription of target mRNAs, SNAI1, VIM, and CDH2, regardless of autophagy status. The imbalance between protein and mRNA levels indicated the possibility of autophagy-dependent translational regulation. Since protein synthesis consumes large amounts of energy, it is tightly regulated via various cellular signaling pathways such as AMPK and mTOR. Our investigation showed inhibition of autophagy decreased ATP production from OXPHOS and led to the suppression of mRNA translation by phosphorylation of eukaryotic elongation factor 2 (eEF2). These results suggest that A549 non-small cell lung cancer required autophagy to maintain mitochondrial homeostasis during TGF-β1 induced EMT. In conclusion, blocking autophagy decreased energy production and down-regulated proteins synthesis inhibiting TGF-β1 induced EMT.
Prognostic Factors for Overall Survival in Patients with HCV-Related HCC Undergoing Molecular Targeted Therapies: Beyond a Sustained Virological Response
Authors: Minami Yasunori , Aoki Tomoko , Chishina Hirokazu , Takita Masahiro , Hagiwara Satoru , Ida Hiroshi , Ueshima Kazuomi , Nishida Naoshi , Kudo Masatoshi
Published: October 2022

Background: The treatment of the hepatitis C virus (HCV) has reduced the risk of hepatocellular carcinoma (HCC)-related mortality. Many patients with advanced HCC have achieved longer survival through systemic chemotherapy. However, survivors of HCC may develop liver cancer during and after treatment. Therefore, the present study investigated prognostic factors for survival in patients with HCV-related HCC in the new era of molecular targeted therapy. Methods: A total of 359 patients with HCV-related HCC treated with first-line chemotherapy were reviewed. A Cox proportional hazards model and Kaplan–Meier curve were used to identify prognostic factors associated with survival outcomes. Results: The median follow-up duration was 16.0 months (range, 1.0–115.7) and the median duration of first-line systemic therapy was 3.73 months (range, 0.7–86.9). The achievement of a sustained virological response (SVR) (p  <  0.001), albumin–bilirubin (ALBI) grade II/III (p  <  0.001), Barcelona Clinic Liver Cancer (BCLC) stage C (p  =  0.005), extrahepatic spread (p < 0.001), baseline AFP (alpha-fetoprotein) level ≥ 90 (p = 0.038), baseline DCP (des-γ-carboxy prothrombin) level ≥ 500 (p < 0.001), and a fibrosis-4 (FIB-4) index ≥ 4 (p  =  0.003) were identified as prognostic factors for overall survival. Conclusions: The achievement of SVR was most strongly associated with overall survival. Other factors, such as the BCLC stage, extrahepatic spread, baseline tumor marker (AFP/DCP) levels, ALBI grade, and FIB-4 index need to be considered in the management of patients with HCV-related HCC.