bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor Immune Microenvironment in Gynecologic Cancers
Authors: Margul Daniel , Yu Camilla , AlHilli Mariam M.
Published: July 2023

Gynecologic cancers have varying response rates to immunotherapy due to the heterogeneity of each cancer’s molecular biology and features of the tumor immune microenvironment (TIME). This article reviews key features of the TIME and its role in the pathophysiology and treatment of ovarian, endometrial, cervical, vulvar, and vaginal cancer. Knowledge of the role of the TIME in gynecologic cancers has been rapidly developing with a large body of preclinical studies demonstrating an intricate yet dichotomous role that the immune system plays in either supporting the growth of cancer or opposing it and facilitating effective treatment. Many targets and therapeutics have been identified including cytokines, antibodies, small molecules, vaccines, adoptive cell therapy, and bacterial-based therapies but most efforts in gynecologic cancers to utilize them have not been effective. However, with the development of immune checkpoint inhibitors, we have started to see the rapid and successful employment of therapeutics in cervical and endometrial cancer. There remain many challenges in utilizing the TIME, particularly in ovarian cancer, and further studies are needed to identify and validate efficacious therapeutics.
15-Year Experience of Distal Pancreatectomy with Celiac Axis Resection (DP-CAR) for Pancreatic Cancer—A Korean Nationwide Investigation
Authors: Yoon So Jeong , Park Sang-Jae , Yoon Yoo-Seok , Hong Tae-Ho , Jang Jin-Young , Kim Hee Joon , Heo Jin Seok , Hwang Dae Wook , Han In Woong
Published: July 2023

Background: As systemic treatment for pancreatic cancer advances, distal pancreatectomy with celiac axis resection (DP-CAR) has been considered a curative-intent surgical option for advanced pancreatic cancer. This study aimed to review the surgical and oncologic outcomes of patients undergoing DP-CAR based on Korean nationwide data. Methods: We collected the data of patients who underwent DP-CAR for pancreatic cancer between 2007 and 2021 at seven major hospitals in Korea. The clinicopathological characteristics, postoperative complications, and data on the survival of the patients were retrospectively reviewed. Logistic regression analysis was performed to identify risk factors for postoperative complications and survival. Results: A total of 75 patients, consisting mainly of borderline resectable (n = 32) or locally advanced (n = 30) pancreatic cancer, were included in the analysis. Forty-two (56.0%) patients underwent neoadjuvant treatment (NAT). Twenty (26.7%) patients experienced Clavien–Dindo grade ≥ 3 complications, including four patients with ischemic gastropathy, two with hepatic ischemia, and two procedure-related mortalities. Neoadjuvant chemotherapy increased the risk of postoperative complications (p = 0.028). The median recurrence-free and overall survival were 7 and 19 months, with a 5-year survival rate of 13% and 24%, respectively. In the NAT group, a decrease in CA 19-9 and the post-NAT maximum standardized uptake value (SUVmax) in positron emission tomography were associated with survival after surgical resection. Conclusions: Despite the possibility of major complications, DP-CAR could be a feasible option for achieving curative resection with fair survival outcomes in patients with borderline resectable or locally advanced pancreatic cancer. Further studies investigating the safety of the procedure and identifying proper surgical candidates with potential survival gains are necessary.
Grey Matter Reshaping of Language-Related Regions Depends on Tumor Lateralization
Authors: Manso-Ortega Lucía , De Frutos-Sagastuy Laura , Gisbert-Muñoz Sandra , Salamon Noriko , Qiao Joe , Walshaw Patricia , Quiñones Ileana , Połczyńska Monika M.
Published: July 2023

A brain tumor in the left hemisphere can decrease language laterality as assessed through fMRI. However, it remains unclear whether or not this decreased language laterality is associated with a structural reshaping of the grey matter, particularly within the language network. Here, we examine if the disruption of the language hubs exclusively affects the macrostructural properties of the contralateral homologues or whether it affects both hemispheres. This study uses voxel-based morphometry applied to high-resolution MR T1-weighted MPRAGE images from 31 adult patients’ left hemisphere, which is dominant for language. Eighteen patients had brain tumors in the left hemisphere, and thirteen had tumors in the right hemisphere. A cohort of 71 healthy individuals matched with respect to age and sex was used as a baseline. We defined 10 ROIs per hemisphere involved in language function. Two separate repeated-measure ANOVAs were conducted with the volume per region as the dependent variable. For the patients, tumor lateralization (right versus left) served as a between-subject factor. The current study demonstrated that the presence of a brain tumor generates global volumetric changes affecting the left language regions and their contralateral homologues. These changes are mediated by the lateralization of the lesion. Our findings suggest that functional mechanisms are supported by the rearrangement of the grey matter.
Supportive Care: The “Keystone” of Modern Oncology Practice
Authors: Scotté Florian , Taylor Amy , Davies Andrew
Published: July 2023

The Multinational Association of Supportive Care in Cancer (MASCC) defines supportive care as “the prevention and management of the adverse effects of cancer and its treatment. This includes management of physical and psychological symptoms and side effects across the continuum of the cancer journey from diagnosis through treatment to post-treatment care. Supportive care aims to improve the quality of rehabilitation, secondary cancer prevention, survivorship, and end-of-life care”. This article will provide an overview of modern supportive care in cancer, discussing its definition, its relationship with palliative care, models of care, “core” service elements (multi-professional/multidisciplinary involvement), the evidence that supportive care improves morbidity, quality of life, and mortality in various groups of patients with cancer, and the health economic benefits of supportive care. The article will also discuss the current and future challenges to providing optimal supportive care to all oncology patients.
Environmental Determinants of Ferroptosis in Cancer
Authors: Setayeshpour Yasaman , Lee Yunji , Chi Jen-Tsan
Published: July 2023

Given the enormous suffering and death associated with human cancers, there is an urgent need for novel therapeutic approaches to target tumor growth and metastasis. While initial efforts have focused on the dysregulated oncogenic program of cancer cells, recent focus has been on the modulation and targeting of many “cancer-friendly,” non-genetic tumor microenvironmental factors, which support and enable tumor progression and metastasis. Two prominent examples are anti-angiogenesis and immunotherapy that target tumor-supporting vascularization and the immune-suppressive tumor microenvironment (TME), respectively. Lately, there has been significant interest in the therapeutic potential of ferroptosis, a natural tumor suppression mechanism that normally occurs as a result of oxidative stress, iron imbalance, and accumulation of lipid peroxides. While numerous studies have identified various cell intrinsic mechanisms to protect or promote ferroptosis, the role of various TME stress factors are also recently recognized to modulate the tumor cells’ susceptibility to ferroptosis. This review aims to compile and highlight evidence of these factors, how various TME stresses affect ferroptosis, and their implications in various stages of tumor development and expected response to ferroptosis-triggering therapeutics under development. Consequently, understanding ways to enhance ferroptosis sensitivity both intracellularly and in the TME may optimize therapeutic sensitivity to minimize or prevent tumor growth and metastasis.
Front-Line Tyrosine Kinase Inhibitors in Pediatric Chronic Myeloid Leukemia: A Study on Efficacy and Safety
Authors: Yoo Jae Won , Jo Suejung , Ahn Moon Bae , Kim Seongkoo , Lee Jae Wook , Kim Myungshin , Cho Bin , Chung Nack-Gyun
Published: July 2023

We conducted a retrospective study on 51 pediatric patients with newly diagnosed chronic myeloid leukemia chronic phase or accelerated phase. The patients were classified into the IMA group (N = 33), treated with imatinib, and the DSA group (N = 18), treated with dasatinib, as front-line tyrosine kinase inhibitors (TKIs). At 12 months, the rates of complete cytogenetic response were similar between the IMA group (92.3%) and DSA group (100%) (p = 0.305). However, the rate of early molecular response was higher in the DSA group than in the IMA group (100.0% vs. 80.0%, p = 0.043). By 12 and 24 months, the DSA group showed faster and higher cumulative rates of both major (DSA group: 72.2% and 100%, respectively; IMA group: 41.2% and 68.7%, respectively; p = 0.002) and deep molecular responses (DSA group: 26.0% and 43.6%, respectively; IMA group: 13.8% and 17.5%, respectively; p = 0.004). Both TKIs were well tolerated. Although the height standard deviation scores decreased in both groups, the height decline was greater in the DSA group between one and two years from the start of TKI therapy. In this study, dasatinib achieved faster and higher molecular responses with an acceptable safety profile. Further follow-up is necessary to assess the long-term outcomes of TKI treatment in children.
Extracellular Matrix Collagen I Differentially Regulates the Metabolic Plasticity of Pancreatic Ductal Adenocarcinoma Parenchymal Cell and Cancer Stem Cell
Authors: Tavares-Valente Diana , Cannone Stefania , Greco Maria Raffaella , Carvalho Tiago Miguel Amaral , Baltazar Fátima , Queirós Odília , Agrimi Gennaro , Reshkin Stephan J. , Cardone Rosa Angela
Published: July 2023

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of less than 10 percent largely due to the intense fibrotic desmoplastic reaction, characterized by high levels of extracellular matrix (ECM) collagen I that constitutes a niche for a subset of cancer cells, the cancer stem cells (CSCs). Cancer cells undergo a complex metabolic adaptation characterized by changes in metabolic pathways and biosynthetic processes. The use of the 3D organotypic model in this study allowed us to manipulate the ECM constituents and mimic the progression of PDAC from an early tumor to an ever more advanced tumor stage. To understand the role of desmoplasia on the metabolism of PDAC parenchymal (CPC) and CSC populations, we studied their basic metabolic parameters in organotypic cultures of increasing collagen content to mimic in vivo conditions. We further measured the ability of the bioenergetic modulators (BMs), 2-deoxyglucose, dichloroacetate and phenformin, to modify their metabolic dependence and the therapeutic activity of paclitaxel albumin nanoparticles (NAB-PTX). While all the BMs decreased cell viability and increased cell death in all ECM types, a distinct, collagen I-dependent profile was observed in CSCs. As ECM collagen I content increased (e.g., more aggressive conditions), the CSCs switched from glucose to mostly glutamine metabolism. All three BMs synergistically potentiated the cytotoxicity of NAB-PTX in both cell lines, which, in CSCs, was collagen I-dependent and the strongest when treated with phenformin + NAB-PTX. Metabolic disruption in PDAC can be useful both as monotherapy or combined with conventional drugs to more efficiently block tumor growth.
Prognostic Values of Tissue and Serum Angiogenic Growth Factors Depend on the Phenotypic Subtypes of Colorectal Cancer
Authors: Kasurinen Jussi Herman , Hagström Jaana , Kaprio Tuomas , Jalkanen Sirpa , Salmi Marko , Böckelman Camilla , Haglund Caj
Published: July 2023

We classified colorectal cancer (CRC) patients into four phenotypic subgroups and investigated the prognostic value of angiogenic growth factors across subgroups. Preoperative serum concentrations and tissue expressions of VEGF, bFGF, and PDGF-bb were determined among 322 CRC patients. We classified patients into phenotypic subgroups (immune, canonical, metabolic, and mesenchymal) according to a method described in our earlier work. Among the metabolic subgroup, patients with high serum concentrations of VEGF, bFGF, or PDGF-bb exhibited a significantly improved prognosis. Moreover, those with high VEGF tissue expressions exhibited a significantly improved prognosis among patients in the metabolic subgroup. Among immune patients, a high VEGF serum expression is associated with a worse prognosis. A high serum bFGF concentration is associated with a favorable prognostic factor among patients with a canonical tumor phenotype. A high PDGF-bb tissue expression is associated with non-metastasized disease and with the immune, canonical, and metabolic subtypes. To our knowledge, this is the first study to show that the prognostic value of angiogenic growth factors differs between phenotypic subtypes.
The Vermiform Appendix and Its Pathologies
Authors: Constantin Marian , Petrescu Livia , Mătanie Cristina , Vrancianu Corneliu Ovidiu , Niculescu Adelina-Gabriela , Andronic Octavian , Bolocan Alexandra
Published: July 2023

The vermiform appendix is a muscular cylindrical structure originating near the junction of the cecum and ileum, averaging 9 cm (5–35 cm) in size. As the most mobile viscera, it can adopt several positions, the most common being the retrocecal position. Perceived as an atavistic organ lacking physiological relevance, the vermiform appendix appears to be involved in immune function, serving in the maturation of B lymphocytes and the production of immunoglobulin A, in endocrine function, excreting amines and hormones in the 2–3 mL of mucus secreted daily, and in digestive function, by storing beneficial bacteria from where they can recolonize the colon. With a lumen of about 6 mm, the vermiform appendix has a reduced storage capacity, so any blockage of the appendix with fecoliths (fecaliths), seeds derailed from the colon, or enlarged lymph nodes prevents drainage and intraluminal accumulation of secreted mucus. Unable to relax, the appendix wall severely limits its intraluminal volume, so mucus accumulation leads to inflammation of the appendix, known generically as appendicitis. In addition, the vermiform appendix may be the site of the development of neoplastic processes, which may or may not involve mucus production, some of which can significantly affect the standard of living and ultimately lead to death. In general, mucinous tumors may have a better prognosis than non-mucinous tumors. This review takes a comprehensive path, starting by describing the anatomy and embryology of the vermiform appendix and further detailing its inflammatory pathologies, pathologies related to congenital anomalies, and appendix tumors, thus creating an up-to-date framework for better understanding, diagnosis, and treatment of these health problems.
KIT and PDGFRA Variants and the Survival of Patients with Gastrointestinal Stromal Tumor Treated with Adjuvant Imatinib
Authors: Joensuu Heikki
Published: July 2023

Adjuvant imatinib improves the recurrence-free survival and overall survival (OS) of patients with gastrointestinal stromal tumors (GISTs) who have a high risk of recurrence after surgery and is now considered standard treatment. Yet, OS benefit has been demonstrated in only one randomized study, the Scandinavian Sarcoma Group XVIII/AIO trial, where patients with high-risk GISTs were allocated to either 1 year or 3 years of adjuvant imatinib. SSGXVIII/AIO is also the only randomized trial in which adjuvant imatinib duration exceeding 2 years was evaluated. In this trial, the 3-year treatment led to a 45% reduction in the risk of death during the first 10 years that followed random allocation even though some of the patients did not have GISTs at tumor histology review, had mutations now known to be imatinib-resistant or had non-localized disease at study entry. In the subgroup of patients who had KIT exon 11 deletion/indel mutation, the reduction in the risk of death was 66% in favor of the longer treatment. Proper patient selection is of crucial importance since many patients are cured with surgery. Little evidence for OS benefit is available from randomized trials for patients whose GIST harbors KIT exon 9 mutation, KIT insertion mutation, PDGFRA D842V mutation, or lacks KIT and PDGFRA mutations. Adjuvant imatinib improves OS substantially if high-risk GISTs can be identified, treatment duration is long enough, and GISTs harbor an imatinib-sensitive mutation.
CBCT-Based Dose Monitoring and Adaptive Planning Triggers in Head and Neck PBS Proton Therapy
Authors: Reiners Keaton , Dagan Roi , Holtzman Adam , Bryant Curtis , Andersson Sebastian , Nilsson Rasmus , Hong Liu , Johnson Perry , Zhang Yawei
Published: July 2023

Purpose: To investigate the feasibility of using cone-beam computed tomography (CBCT)-derived synthetic CTs to monitor the daily dose and trigger a plan review for adaptive proton therapy (APT) in head and neck cancer (HNC) patients. Methods: For 84 HNC patients treated with proton pencil-beam scanning (PBS), same-day CBCT and verification CT (vfCT) pairs were retrospectively collected. The ground truth CT (gtCT) was created by deforming the vfCT to the same-day CBCT, and it was then used as a dosimetric baseline and for establishing plan review trigger recommendations. Two different synthetic CT algorithms were tested; the corrected CBCT (corrCBCT) was created using an iterative image correction method and the virtual CT (virtCT) was created by deforming the planning CT to the CBCT, followed by a low-density masking process. Clinical treatment plans were recalculated on the image sets for evaluation. Results: Plan review trigger criteria for adaptive therapy were established after closely reviewing the cohort data. Compared to the vfCT, the corrCBCT and virtCT reliably produced dosimetric data more similar to the gtCT. The average discrepancy in D99 for high-risk clinical target volumes (CTV) was 1.1%, 0.7%, and 0.4% and for standard-risk CTVs was 1.8%, 0.5%, and 0.5% for the vfCT, corrCBCT, and virtCT, respectively. Conclusion: Streamlined APT has been achieved with the proposed plan review criteria and CBCT-based synthetic CT workflow.
FLASH Radiotherapy and the Use of Radiation Dosimeters
Authors: Siddique Sarkar , Ruda Harry E. , Chow James C. L.
Published: July 2023

Radiotherapy (RT) using ultra-high dose rate (UHDR) radiation, known as FLASH RT, has shown promising results in reducing normal tissue toxicity while maintaining tumor control. However, implementing FLASH RT in clinical settings presents technical challenges, including limited depth penetration and complex treatment planning. Monte Carlo (MC) simulation is a valuable tool for dose calculation in RT and has been investigated for optimizing FLASH RT. Various MC codes, such as EGSnrc, DOSXYZnrc, and Geant4, have been used to simulate dose distributions and optimize treatment plans. Accurate dosimetry is essential for FLASH RT, and radiation detectors play a crucial role in measuring dose delivery. Solid-state detectors, including diamond detectors such as microDiamond, have demonstrated linear responses and good agreement with reference detectors in UHDR and ultra-high dose per pulse (UHDPP) ranges. Ionization chambers are commonly used for dose measurement, and advancements have been made to address their response nonlinearities at UHDPP. Studies have proposed new calculation methods and empirical models for ion recombination in ionization chambers to improve their accuracy in FLASH RT. Additionally, strip-segmented ionization chamber arrays have shown potential for the experimental measurement of dose rate distribution in proton pencil beam scanning. Radiochromic films, such as GafchromicTM EBT3, have been used for absolute dose measurement and to validate MC simulation results in high-energy X-rays, triggering the FLASH effect. These films have been utilized to characterize ionization chambers and measure off-axis and depth dose distributions in FLASH RT. In conclusion, MC simulation provides accurate dose calculation and optimization for FLASH RT, while radiation detectors, including diamond detectors, ionization chambers, and radiochromic films, offer valuable tools for dosimetry in UHDR environments. Further research is needed to refine treatment planning techniques and improve detector performance to facilitate the widespread implementation of FLASH RT, potentially revolutionizing cancer treatment.
Factors Affecting Health-Related Quality of Life among Survivors of Non-Hodgkin Lymphoma: A Population-Based Study
Authors: Wasse Stephane Kroudia , Mounier Morgane , Assogba Emerline , Rossi Cédric , Adnet Johan , Gauthier Sophie , Girard Stephanie , Atsou Kueshivi Midodji , Dabakuyo-Yonli Tienhan Sandrine , Maynadie Marc
Published: July 2023

Purpose: To describe Health-Related Quality of Life (HRQoL) and to identify the association between sociodemographic, clinical and psychosocial factors, and self-reported HRQoL among NHL survivors. Methods: The data of the cancer registry specialized in hematological malignancies in Côte d’Or (France) were used to identify all patients diagnosed with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) from 2010 to 2017. Patients were invited to complete SF-12 and other questionnaires. Results: The HRQoL of NHL survivors was poorer than that of the French general population (p < 0.05) in vitality (48 vs. 56), general health (56 vs. 63), role physical scores (60 vs. 70), role emotional scores (64 vs. 72) and the Mental Component Scale (45 vs. 49). The mean difference in physical functioning decreased per unit increase in age (β = −1.1 (0.3); p < 0.001). Men had better vitality than women (β = 12.4 (6.1); p = 0.04) and the high education level was associated with greater role emotional scores (β = 14.1 (5.4); p = 0.01). Symptoms of anxiety and depression were associated with poorer HRQoL. The satisfaction of social support was associated with significantly greater scores on mental health (β = 17.3 (5.1); p = 0.001) and social functioning (β = 15.7 (7.8); p = 0.04). Socioeconomic deprivation was associated with poorer general health (β = −12.8 (5.2); p = 0.01). Conclusions: From 3 to 11 years post-diagnosis, the main factors found to be associated with poor HRQoL of NHL survivors were age, sex, presence of anxiety, depression and economic problems. These findings suggest the need for supportive care to improve HRQOL and the consideration of these problems when developing care plans for NHL survivors.
Antibody–Drug Conjugates: A Review of Approved Drugs and Their Clinical Level of Evidence
Authors: Gogia Pooja , Ashraf Hamza , Bhasin Sidharth , Xu Yiqing
Published: July 2023

Antibody–drug conjugates (ADCs) are an innovative family of agents assembled through linking cytotoxic drugs (payloads) covalently to monoclonal antibodies (mAbs) to be delivered to tumor tissue that express their particular antigen, with the theoretical advantage of an augmented therapeutic ratio. As of June 2023, eleven ADCs have been approved by the Food and Drug Administration (FDA) and are on the market. These drugs have been added to the therapeutic armamentarium of acute myeloblastic and lymphoblastic leukemias, various types of lymphoma, breast, gastric or gastroesophageal junction, lung, urothelial, cervical, and ovarian cancers. They have proven to deliver more potent and effective anti-tumor activities than standard practice in a wide variety of indications. In addition to targeting antigen-expressing tumor cells, bystander effects have been engineered to extend cytotoxic killing to low-antigen-expressing or negative tumor cells in the heterogenous tumor milieu. Inevitably, myelosuppression is a common side effect with most of the ADCs due to the effects of the cytotoxic payload. Also, other unique side effects are specific to the tissue antigen that is targeted for, such as the cardiac toxicity with Her-2 targeting ADCs, and the hemorrhagic side effects with the tissue factor (TF) targeting Tisotumab vedotin. Further exciting developments are centered in the strategies to improve the tolerability and efficacy of the ADCs to improve the therapeutic window; as well as the development of novel payloads including (1) peptide–drug conjugates (PDCs), with the peptide replacing the monoclonal antibody, rendering greater tumor penetration; (2) immune-stimulating antibody conjugates (ISACs), which upon conjugation of the antigen, cause an influx of pro-inflammatory cytokines to activate dendritic cells and harness an anti-tumor T-cell response; and (3) the use of radioactive isotopes as a payload to enhance cytotoxic activity.
Innovative Breakthroughs for the Treatment of Advanced and Metastatic Synovial Sarcoma
Authors: Landuzzi Lorena , Manara Maria Cristina , Pazzaglia Laura , Lollini Pier-Luigi , Scotlandi Katia
Published: July 2023

Synovial sarcoma (SyS) is a rare aggressive soft tissue sarcoma carrying the chromosomal translocation t(X;18), encoding the fusion transcript SS18::SSX. The fusion oncoprotein interacts with both BAF enhancer complexes and polycomb repressor complexes, resulting in genome-wide epigenetic perturbations and a unique altered genetic signature. Over 80% of the patients are initially diagnosed with localized disease and have a 5-year survival rate of 70–80%, but metastatic relapse occurs in 50% of the cases. Advanced, unresectable, or metastatic disease has a 5-year survival rate below 10%, representing a critical issue. This review summarizes the molecular mechanisms behind SyS and illustrates current treatments in front line, second line, and beyond settings. We analyze the use of immune check point inhibitors (ICI) in SyS that do not behave as an ICI-sensitive tumor, claiming the need for predictive genetic signatures and tumor immune microenvironment biomarkers. We highlight the clinical translation of innovative technologies, such as proteolysis targeting chimera (PROTAC) protein degraders or adoptive transfer of engineered immune cells. Adoptive cell transfer of engineered T-cell receptor cells targeting selected cancer/testis antigens has shown promising results against metastatic SyS in early clinical trials and further improvements are awaited from refinements involving immune cell engineering and tumor immune microenvironment enhancement.
miR-4284 Functions as a Tumor Suppressor in Renal Cell Carcinoma Cells by Targeting Glutamate Decarboxylase 1
Authors: Choi Sujin , Kim Kyeongmi , Yeo Hyunjeong , Lee Gyurim , Kim Isaac , Oh Jisu , An Hyun-Ju , Lee Soonchul
Published: July 2023

MicroRNAs (miRNAs) play a crucial role as oncogenic or tumor suppressors in the pathogenesis and progression of tumors. However, few studies have investigated the exact role of miR-4284 in renal cell carcinoma (RCC). We aimed to investigate the role of miR-4284 as a tumor suppressor in renal cancer cell lines. A498 and Caki-1 were transfected with miR-4284. The Cell Counting Kit-8, colony formation, apoptosis assays, and quantitative reverse transcription–polymerase chain reaction were used to evaluate tumor growth-inhibiting functions. The wound-healing, transwell, and sphere-formation assays were conducted to investigate tumorigenic characteristics. The potential target genes of miR-4284 were predicted and experimentally verified. A xenograft experiment was performed to estimate the tumor-growth-suppressive function of miR-4284. miR-4284 overexpression suppressed proliferation, induced apoptosis, and suppressed tumorigenic features of renal cancer cells. Glutamate decarboxylase 1 (GAD1) was directly targeted by miR-4284. A xenograft mouse model injected with Caki-1 cells transfected with miR-4284 showed significantly decreased tumor growth rate and volume. miR-4284 affected tumor growth, metastasis, and apoptosis of renal cancer cells in vitro and in vivo. These findings highlight the potential of miR-4284 as a target for anticancer miRNA therapeutics in RCC.
Hepatic Metastasectomy in Squamous Cell Carcinoma of the Anal Canal: A Case Series of a Curative Approach
Authors: Rogers Jane E. , Sirisaengtaksin Amanda , Leung Michael , Morris Van K. , Xiao Lianchun , Huey Ryan , Wolff Robert , Eng Cathy , Vauthey Jean Nicolas , Tzeng Ching-Wei D. , Johnson Benny
Published: July 2023

Background: Squamous cell carcinoma of the anal canal (SCCA) is rare. Most cases are diagnosed in a localized setting. Metastatic SCCA is rare, and investigation has been limited in the past for these patients. We believe that hepatic-only metastatic disease could have a unique treatment landscape compared to diseases with diffuse metastatic involvement. Here, we describe cases at our institution. Methods: We reviewed eight SCCA cases with hepatic-only metastatic disease (diagnosed February 2018–January 2022). The objectives were to determine the overall survival and disease-free survival with this approach. Results: The median age was 62 years old (yo). Patients had an ECOG of 0–1. All patients received definitive chemoradiation to their primary anal tumor. A median of three months of neoadjuvant systemic therapy was provided. All patients had a response on their first scan after systemic therapy. Sixty-two percent received carboplatin + paclitaxel. A complete pathologic response was seen in 62% of patients. At their last follow-up, all patients were alive. Three patients had recurrent disease. The estimated 1-year disease-free survival probability was 56.2%. Conclusion: Our report shows the feasibility of a curative-intent approach for patients with hepatic-only metastatic SCCA following the neoadjuvant application of carboplatin + paclitaxel. This approach appears promising in these select patients and warrants further investigation.
A Deep Learning Onion Peeling Approach to Measure Oral Epithelium Layer Number
Authors: Zhang Xinyi , Gleber-Netto Frederico O. , Wang Shidan , Jin Kevin W. , Yang Donghan M. , Gillenwater Ann M. , Myers Jeffrey N. , Ferrarotto Renata , Pickering Curtis R. , Xiao Guanghua
Published: July 2023

Head and neck squamous cell carcinoma (HNSCC), specifically in the oral cavity (oral squamous cell carcinoma, OSCC), is a common, complex cancer that significantly affects patients’ quality of life. Early diagnosis typically improves prognoses yet relies on pathologist examination of histology images that exhibit high inter- and intra-observer variation. The advent of deep learning has automated this analysis, notably with object segmentation. However, techniques for automated oral dysplasia diagnosis have been limited to shape or cell stain information, without addressing the diagnostic potential in counting the number of cell layers in the oral epithelium. Our study attempts to address this gap by combining the existing U-Net and HD-Staining architectures for segmenting the oral epithelium and introducing a novel algorithm that we call Onion Peeling for counting the epithelium layer number. Experimental results show a close correlation between our algorithmic and expert manual layer counts, demonstrating the feasibility of automated layer counting. We also show the clinical relevance of oral epithelial layer number to grading oral dysplasia severity through survival analysis. Overall, our study shows that automated counting of oral epithelium layers can represent a potential addition to the digital pathology toolbox. Model generalizability and accuracy could be improved further with a larger training dataset.
Identification of a Novel Eight-Gene Risk Model for Predicting Survival in Glioblastoma: A Comprehensive Bioinformatic Analysis
Authors: Dang Huy-Hoang , Ta Hoang Dang Khoa , Nguyen Truc Tran Thanh , Wang Chih-Yang , Lee Kuen-Haur , Le Nguyen Quoc Khanh
Published: July 2023

Glioblastoma (GBM) is one of the most progressive and prevalent cancers of the central nervous system. Identifying genetic markers is therefore crucial to predict prognosis and enhance treatment effectiveness in GBM. To this end, we obtained gene expression data of GBM from TCGA and GEO datasets and identified differentially expressed genes (DEGs), which were overlapped and used for survival analysis with univariate Cox regression. Next, the genes’ biological significance and potential as immunotherapy candidates were examined using functional enrichment and immune infiltration analysis. Eight prognostic-related DEGs in GBM were identified, namely CRNDE, NRXN3, POPDC3, PTPRN, PTPRN2, SLC46A2, TIMP1, and TNFSF9. The derived risk model showed robustness in identifying patient subgroups with significantly poorer overall survival, as well as those with distinct GBM molecular subtypes and MGMT status. Furthermore, several correlations between the expression of the prognostic genes and immune infiltration cells were discovered. Overall, we propose a survival-derived risk score that can provide prognostic significance and guide therapeutic strategies for patients with GBM.
Steroidal Saponins: Naturally Occurring Compounds as Inhibitors of the Hallmarks of Cancer
Authors: Bouabdallah Salwa , Al-Maktoum Amna , Amin Amr
Published: July 2023

Cancer is a global health burden responsible for an exponentially growing number of incidences and mortalities, regardless of the significant advances in its treatment. The identification of the hallmarks of cancer is a major milestone in understanding the mechanisms that drive cancer initiation, development, and progression. In the past, the hallmarks of cancer have been targeted to effectively treat various types of cancers. These conventional cancer drugs have shown significant therapeutic efficacy but continue to impose unfavorable side effects on patients. Naturally derived compounds are being tested in the search for alternative anti-cancer drugs. Steroidal saponins are a group of naturally occurring compounds that primarily exist as secondary metabolites in plant species. Recent studies have suggested that steroidal saponins possess significant anti-cancer capabilities. This review aims to summarize the recent findings on steroidal saponins as inhibitors of the hallmarks of cancer and covers key studies published between the years 2014 and 2024. It is reported that steroidal saponins effectively inhibit the hallmarks of cancer, but poor bioavailability and insufficient preclinical studies limit their utilization.
A Bibliometric Analysis of the Oligometastatic State over the Last Two Decades: A Shifting Paradigm for Oncology? An AIRO Oligometastatic Study Group
Authors: Marvaso Giulia , Mastroleo Federico , Corrao Giulia , Zaffaroni Mattia , Vincini Maria Giulia , Borghetti Paolo , Cuccia Francesco , Federico Manuela , Montesi Giampaolo , Pontoriero Antonio , Franceschini Davide , Franzese Ciro , Scorsetti Marta , Jereczek-Fossa Barbara Alicja
Published: July 2023

The term “oligometastasis” represents a relatively novel idea, which denotes a condition characterized by cancer dissemination with a limited number of lesions (usually fewer than five). The aim of the present study is to report a bibliometric analysis of the oligometastatic disease/state, incorporating all relevant studies on the topic for more than 20 years. The research strategy included at least one the terms “Oligmetastases”, “Oligometastasis”, “Oligometastatic”, “Oligoprogression, “Oligoprogressive”, “Oligorecurrent”, or “Oligorecurrency” in the title, abstract, and/or keywords. All English-language documents from 1 January 1995 (the year of the earliest available document in Scopus) to 31 December 2022 were considered for the analysis. R code (R version 4.2.0) with R Studio (version 2022.12.0-353) and the Bibliometrix package (version 4.0.1) were used for the analysis. A total of 3304 documents, mainly articles (n = 2083, 63.0%) and reviews (n = 813, 24.6%), were collected from 1995 to 2022. The average annual growth rate of literature on the topic was 26.7%. Overall 15,176 authors published on the topic, with an average of eight authors/publication. From 1995, 69 countries contributed to the literature, with the USA and Italy being the top contributors. Among all keywords used by authors, the top three were oligometastases (19%), SBRT (18%), and radiation therapy (8%). Themes regarding “locoregional treatment”, “organ motion”, and “immunotherapy” were the most recent trend topics, mainly developed from 2019 to 2022, while “high-dose chemotherapy”, “whole-brain radiotherapy”, and “metastatic breast cancer” saw their main development during 2009–2018. Our study shows the exceptionally flourishing scientific production on the oligometastatic state, summarizing the most influential studies and highlighting the future developments and interests. This analysis will serve as a benchmark to identify this area for the attention of researchers worldwide and contribute to the increasing scientific work.
Synthesis of Eugenol Ethyl Ether by Ethylation of Eugenol with Diethyl Carbonate over KF/γ-Al2O3 Catalyst
Authors: Zhang Zhihai , Zhang Qinyong , Liang Jilei , Ding Tingting , Wang Jiaying , Zhu Kai
Published: July 2023

A KF/γ-Al2O3 solid base catalyst was prepared by wet impregnation and applied to the synthesis of eugenol ethyl ether (EEE) from eugenol and diethyl carbonate. By measuring the yield of eugenol ethyl ether, we investigated the effects of the catalyst active component, impregnation temperature, KF impregnation concentration, impregnation time, and calcination temperature on catalyst performance. The results showed that the KF/γ-Al2O3 catalyst can adequately facilitate the conversion of eugenol to EEE. The characterizations of the catalysts were examined by means of X-ray diffraction (XRD) and scanning electron microscopy (SEM). The characterizations of EEE were examined by nuclear magnetic resonance spectrometry (H1-NMR), gas chromatography–mass spectrometer (GC-MS) and Fourier-transform infrared spectroscopy (FT-IR). It was found that the KF/Al2O3 catalyst (impregnation temperature 60 °C, KF impregnation concentration 40%, impregnation time 8 h, and calcination temperature 450 °C) showed the best effect. The yield of EEE remained 51.2% after recycling the supported catalyst three times.
Application of Heterogeneous Catalysis in Formic Acid-Based Hydrogen Cycle System
Authors: Wang Zhenzhen , Qian Junfeng , Sun Zhonghua , Zhang Zhihui , He Mingyang , Chen Qun
Published: July 2023

H2 has aroused significant attention as an unpolluted and renewable energy carrier. However, the efficient storage and controllable release of H2 are urgent to be addressed. Through the hydrogenation of CO2 (bicarbonate) to produce formic acid (formate) and reverse dehydrogenation reactions, a carbon-neutral formic acid-based hydrogen cycle system can be established. Given the excellent recyclability and facile separation of heterogeneous catalysis, the development of heterogeneous catalysts for these reversible interconversions is thoroughly summarized, with a special focus on the structure–activity relationship and the mechanistic insight. Finally, the challenges and opportunities surrounding the formic acid-based hydrogen cycle system are discussed. It is hoped that this review will provide guidance and an idea for the design and development of efficient heterogeneous catalysts for the carbon-neutral H2 storage and release system.
Statins Modulate Microenvironmental Cues Driving Macrophage Polarization in Simulated Periodontal Inflammation
Authors: Alkakhan Waleed , Farrar Nico , Sikora Vanessa , Emecen-Huja Pinar , Huja Sarandeep S. , Yilmaz Özlem , Pandruvada Subramanya N.
Published: July 2023

Periodontal disease (PD) is a chronic inflammatory disorder characterized by the destruction of connective tissue, tooth loss, and systemic infections. Clinically, treatment of PD includes control of the etiologic factors via several modalities: initial therapy including scaling and root planing (SRP), corrective phase of surgical treatment, both with and without adjunct antimicrobial/pharmacological agents, followed by a maintenance/supportive periodontal therapy phase. Each treatment phase aims to control oral biofilm by addressing risk factors and etiology. Monotherapy of systemic antibiotics is insufficient compared to their use as an adjunct to SRP. The critical issue of systemic antimicrobial usage includes adverse patient outcomes and increased bacterial resistance. Therefore, alternative adjuncts to periodontal therapy have been sought. Statins are widely prescribed for the treatment of hypercholesterolemia and cardiovascular disease. Statins have demonstrated anti-inflammatory properties and immunomodulatory effects, and a few retrospective studies showed that statin patients exhibit fewer signs of periodontal inflammation than subjects without the medication. Despite the available clinical studies on the local administration of statins for PD, no studies have reported the macrophage polarization response. We have developed a gingival fibroblast–macrophage co-culture model to track macrophage response when exposed to a battery of microenvironmental cues mimicking macrophage polarization/depolarization observed in vivo. Using our model, we demonstrate that simvastatin suppresses macrophage inflammatory response and upregulates tissue homeostasis and M2 macrophage markers. Our findings support the usage of statins to mitigate periodontal inflammation as a valid strategy.
FNBP1 Facilitates Cervical Cancer Cell Survival by the Constitutive Activation of FAK/PI3K/AKT/mTOR Signaling
Authors: Zhang Jun , Li Xin , Zhou Yunfei , Lin Mingming , Zhang Qianying , Wang Yunhong
Published: July 2023

Cervical cancer is the most prevalent gynecological tumor among women worldwide. Although the incidence and mortality of cervical cancer have been declining thanks to the wide-scale implementation of cytological screening, it remains a major challenge in clinical treatment. High viability is one of the leading causes of the chemotherapeutic resistance in cervical cancers. Formin-binding protein 1 (FNBP1) could stimulate F-actin polymerization beneath the curved plasma membrane in the cell migration and endocytosis, which had previously been well defined. Here, FNBP1 was also demonstrated to play a crucial role in cervical cancer cell survival, and the knockdown of which could result in the attenuation of FAK/PI3K/AKT signaling followed by significant apoptotic accumulation and proliferative inhibition. In addition, the epidermal growth factor (hrEGF) abrogated all the biological effects mediated by the silencing of FNBP1 except for the cell adhesion decrease. These findings indicated that FNBP1 plays a key role in maintaining the activity of focal adhesion kinase (FAK) by promoting cell adhesion. The activated FAK positively regulated downstream PI3K/AKT/mTOR signaling, which is responsible for cell survival. Promisingly, FNBP1 might be a potential target against cervical cancer in combination therapy.
Effect of Inflammatory Microenvironment on the Regenerative Capacity of Adipose-Derived Mesenchymal Stem Cells
Authors: Szűcs Diána , Miklós Vanda , Monostori Tamás , Guba Melinda , Kun-Varga Anikó , Póliska Szilárd , Kis Erika , Bende Balázs , Kemény Lajos , Veréb Zoltán
Published: July 2023

Adipose-derived mesenchymal stem cells are increasingly being used in regenerative medicine as cell therapy targets, including in the treatment of burns and ulcers. The regenerative potential of AD-MSCs and some of their immunological properties are known from in vitro studies; however, in clinical applications, cells are used in non-ideal conditions and can behave differently in inflammatory environments, affecting the efficacy and outcome of therapy. Our aim was to investigate and map the pathways that the inflammatory microenvironment can induce in these cells. High-throughput gene expression assays were performed on AD-MSCs activated with LPS and TNFα. Analysis of RNA-Seq data showed that control, LPS-treated and TNFα-treated samples exhibited distinct gene expression patterns. LPS treatment increased the expression of 926 genes and decreased the expression of 770 genes involved in cell division, DNA repair, the cell cycle, and several metabolic processes. TNFα treatment increased the expression of 174 genes and decreased the expression of 383 genes, which are related to cell division, the immune response, cell proliferation, and differentiation. We also map the biological pathways by further investigating the most altered genes using the Gene Ontology and KEGG databases. Secreted cytokines, which are important in the immunological response, were also examined at the protein level, and a functional assay was performed to assess wound healing. Activated AD-MSC increased the secretion of IL-6, IL-8 and CXCL-10, and also the closure of wounds. AD-MSCs presented accelerated wound healing under inflammation conditions, suggesting that we could use this cell in clinical application.
DCUN1D1 Is an Essential Regulator of Prostate Cancer Proliferation and Tumour Growth That Acts through Neddylation of Cullin 1, 3, 4A and 5 and Deregulation of Wnt/Catenin Pathway
Authors: Vava Akhona , Paccez Juliano D. , Wang Yihong , Gu Xuesong , Bhasin Manoj K. , Myers Michael , Soares Nelson C. , Libermann Towia A. , Zerbini Luiz F.
Published: July 2023

Defective in cullin neddylation 1 domain containing 1 (DCUN1D1) is an E3 ligase for the neddylation, a post-translational process similar to and occurring in parallel to ubiquitin proteasome pathway. Although established as an oncogene in a variety of squamous cell carcinomas, the precise role of DCUN1D1 in prostate cancer (PCa) has not been previously explored thoroughly. Here, we investigated the role of DCUN1D1 in PCa and demonstrated that DCUN1D1 is upregulated in cell lines as well as human tissue samples. Inhibition of DCUN1D1 significantly reduced PCa cell proliferation and migration and remarkably inhibited xenograft formation in mice. Applying both genomics and proteomics approaches, we provide novel information about the DCUN1D1 mechanism of action. We identified CUL3, CUL4B, RBX1, CAND1 and RPS19 proteins as DCUN1D1 binding partners. Our analysis also revealed the dysregulation of genes associated with cellular growth and proliferation, developmental, cell death and cancer pathways and the WNT/β-catenin pathway as potential mechanisms. Inhibition of DCUN1D1 leads to the inactivation of β-catenin through its phosphorylation and degradation which inhibits the downstream action of β-catenin, reducing its interaction with Lef1 in the Lef1/TCF complex that regulates Wnt target gene expression. Together our data point to an essential role of the DCUN1D1 protein in PCa which can be explored for potential targeted therapy.
Crystal Structure of the ORP8 Lipid Transport ORD Domain: Model of Lipid Transport
Authors: Eisenreichova Andrea , Klima Martin , Anila Midhun , Koukalova Alena , Humpolickova Jana , Różycki Bartosz , Boura Evzen
Published: July 2023

ORPs are lipid-transport proteins belonging to the oxysterol-binding protein family. They facilitate the transfer of lipids between different intracellular membranes, such as the ER and plasma membrane. We have solved the crystal structure of the ORP8 lipid transport domain (ORD8). The ORD8 exhibited a β-barrel fold composed of anti-parallel β-strands, with three α-helices replacing β-strands on one side. This mixed alpha–beta structure was consistent with previously solved structures of ORP2 and ORP3. A large cavity (≈1860 Å3) within the barrel was identified as the lipid-binding site. Although we were not able to obtain a lipid-bound structure, we used computer simulations based on our crystal structure to dock PS and PI4P molecules into the putative lipid-binding site of the ORD8. Comparative experiments between the short ORD8ΔLid (used for crystallography) and the full-length ORD8 (lid containing) revealed the lid’s importance for stable lipid binding. Fluorescence assays revealed different transport efficiencies for PS and PI4P, with the lid slowing down transport and stabilizing cargo. Coarse-grained simulations highlighted surface-exposed regions and hydrophobic interactions facilitating lipid bilayer insertion. These findings enhance our comprehension of ORD8, its structure, and lipid transport mechanisms, as well as provide a structural basis for the design of potential inhibitors.