bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing a Risk Management Process for General Contractors in the Bidding Stage for Design–Build Projects in Vietnam
Authors: Pham Duy-Hoang , Ly Dang-Huy , Tran Ngoc-Khue , Ahn Yong-Han , Jang Hyeongjae
Published: November 2021

Design–build (DB) projects have become increasingly popular for construction projects in developing countries due to the cost and scheduling advantages and their design optimization ability. As a result, much research has been conducted on improving DB efficiency in terms of cost, scheduling, risk management, etc. However, the existing studies have mainly focused on the owner’s roles, whereas general contractors (GCs) must also take many risks on behalf of owners in DB projects. The adequate identification and assessment of risks before engaging a contractor can increase the likelihood of a project’s success, at least from a DB contractor’s perspective. Therefore, this study interviewed procurement experts to conduct a survey at the local level, then analyzed, developed, and proposed an additional risk management process (RMP) for use by GCs during the bidding process of DB projects. A case study was conducted with a large Vietnamese GC to evaluate the effectiveness of the process and find ways to optimize it in the future. The results of the study showed that risk management during a DB project is imperative. Nevertheless, preparing bids is time-consuming and increases the contingency costs, reducing the competitiveness of the bid prices for contractors. Therefore, depending on the specific project and risk management objectives, an RMP is recommended for adjusting the risk management target to reduce the risk, while still maintaining the competitiveness of the bid prices.
Molecular Targets and Emerging Therapies for Advanced Gallbladder Cancer
Authors: Canale Matteo , Monti Manlio , Rapposelli Ilario Giovanni , Ulivi Paola , Sullo Francesco Giulio , Bartolini Giulia , Tiberi Elisa , Frassineti Giovanni Luca
Published: November 2021

Biliary tract cancers (BTCs), for their low incidence, have been often considered together. Gallbladder cancer (GBC) is the most common biliary tract malignancy, characterized by late diagnosis and poor prognosis, and although it is considered a rare tumor in western countries, other areas of the world show considerable incidence rates. In 2010, results from the large phase III ABC-02 clinical trial on GBC identified the gemcitabine and cisplatin combination as the most effective first-line regimen for both GBC and other BTCs. Since then, various systemic therapies have proven active in BTCs in both first- and second-line settings. Molecular profiling has highlighted important genetic differences between GBC and other BTCs, opening new ways for targeted therapy in advanced disease where standard chemotherapies show marginal benefit. Genome-wide data analysis have shown that GBC molecular landscape offer possible strategies for precision medicine approaches, and a better molecular understanding of the GBC is needed to better stratify patients for treatment. In this review, we discuss the molecular targetable agents for GBC, including the results that emerged by clinical trials exploring new treatment strategies.
Development of a Radiomic-Based Model Predicting Lymph Node Involvement in Prostate Cancer Patients
Authors: Bourbonne Vincent , Jaouen Vincent , Nguyen Truong An , Tissot Valentin , Doucet Laurent , Hatt Mathieu , Visvikis Dimitris , Pradier Olivier , Valéri Antoine , Fournier Georges , Schick Ulrike
Published: November 2021

Significant advances in lymph node involvement (LNI) risk modeling in prostate cancer (PCa) have been achieved with the addition of visual interpretation of magnetic resonance imaging (MRI) data, but it is likely that quantitative analysis could further improve prediction models. In this study, we aimed to develop and internally validate a novel LNI risk prediction model based on radiomic features extracted from preoperative multimodal MRI. All patients who underwent a preoperative MRI and radical prostatectomy with extensive lymph node dissection were retrospectively included in a single institution. Patients were randomly divided into the training (60%) and testing (40%) sets. Radiomic features were extracted from the index tumor volumes, delineated on the apparent diffusion coefficient corrected map and the T2 sequences. A ComBat harmonization method was applied to account for inter-site heterogeneity. A prediction model was trained using a neural network approach (Multilayer Perceptron Network, SPSS v24.0©) combining clinical, radiomic and all features. It was then evaluated on the testing set and compared to the current available models using the Receiver Operative Characteristics and the C-Index. Two hundred and eighty patients were included, with a median age of 65.2 y (45.3–79.6), a mean PSA level of 9.5 ng/mL (1.04–63.0) and 79.6% of ISUP ≥ 2 tumors. LNI occurred in 51 patients (18.2%), with a median number of extracted nodes of 15 (10–19). In the testing set, with their respective cutoffs applied, the Partin, Roach, Yale, MSKCC, Briganti 2012 and 2017 models resulted in a C-Index of 0.71, 0.66, 0.55, 0.67, 0.65 and 0.73, respectively, while our proposed combined model resulted in a C-Index of 0.89 in the testing set. Radiomic features extracted from the preoperative MRI scans and combined with clinical features through a neural network seem to provide added predictive performance compared to state of the art models regarding LNI risk prediction in PCa.
Relationship between Serum Bortezomib Concentration and Emergence of Diarrhea in Patients with Multiple Myeloma and/or AL Amyloidosis
Authors: Fujimoto Yuki , Ueno Shikiko , Oda Kazutaka , Gunda Nao , Shimomura Yumi , Nishimura Yuka , Yamaguchi Ayami , Kuwano Akari , Ito Yuki , Baba Yusuke , Nishigaki Aina , Michiwaki Natsumi , Uchino Shota , Kurogi Kayo , Kawano Yawara , Matsuoka Masao , Saito Hideyuki , Okuno Yutaka , Jono Hirofumi
Published: November 2021

(1) Background: multiple myeloma patients have benefited from bortezomib therapy, though it has often been discontinued owing to diarrhea. The objective of this study was to verify serum bortezomib concentration in the emergence of diarrhea. (2) Methods: this prospective, observational case-control, and monocentric study was performed with an approval by the Ethics Committee of Kumamoto University Hospital in 2015 (No. 1121) from February 2015 to April 2017. (3) Results: twenty-four patients with bortezomib therapy were recruited; eight patients (33.3%) developed diarrhea at day 3 as median. Median measured trough bortezomib concentration at 24 h after first or second dose for patients with or without diarrhea was 0.87 or 0.48 ng/mL, respectively (p = 0.04, Wilcoxon signed rank test). Receiver operation characteristic (ROC) analysis produced the cut-off concentration of 0.857 ng/mL (area under the ROC curve of 0.797, sensitivity of 0.625, specificity of 0.875). The survival curves between patients with and without diarrhea were similar (p = 0.667); those between patients with higher and lower concentration than median value (0.61 ng/mL) were also similar (p = 0.940). (4) Conclusions: this study indicated the possible involvement of serum bortezomib concentration in the emergence of diarrhea in bortezomib therapy in patients with multiple myeloma.
Use of Azacitidine or Decitabine for the Up-Front Setting in Acute Myeloid Leukaemia: A Systematic Review and Meta-Analysis
Authors: Saiz-Rodríguez Miriam , Labrador Jorge , Cuevas Beatriz , Martínez-Cuadrón David , Campuzano Verónica , Alcaraz Raquel , Cano Isabel , Sanz Miguel A. , Montesinos Pau
Published: November 2021

Irruption of decitabine and azacitidine has led to profound changes in the upfront management of older acute myeloid leukaemia (AML). However, they have not been directly compared in a randomised clinical trial. In addition, there are no studies comparing the optimal treatment schedule of each drug in AML. A systematic review and meta-analysis on the efficacy of decitabine and azacitidine monotherapy in newly diagnosed AML was conducted. Randomised controlled trials and retrospective studies were included. A total of 2743 patients from 23 cohorts were analysed (10 cohorts of azacitidine and 13 of decitabine). Similar response rates were observed for azacitidine (38%, 95% CI: 30–47%) compared to decitabine (40%, 95% CI: 32–48%) (p = 0.825). Overall survival (OS) between azacitidine (10.04 months, 95% CI: 8.36–11.72) and decitabine (8.79 months, 95% CI: 7.62–9.96) was also similar (p = 0.386). Patients treated with azacitidine showed a lower median OS when azacitidine was administered for 5 days (6.28 months, 95% CI: 4.23–8.32) compared to the standard 7-day schedule (10.83 months, 95% CI: 9.07–12.59, p = 0.002). Among patients treated with decitabine, response rates and OS were not significantly different between 5-day and 10-day decitabine regimens. Despite heterogeneity between studies, we found no differences in response rates and OS in AML patients treated with azacitidine or decitabine.
Cyclin E1 in Murine and Human Liver Cancer: A Promising Target for Therapeutic Intervention during Tumour Progression
Authors: Sonntag Roland , Penners Christian , Kohlhepp Marlene , Haas Ute , Lambertz Daniela , Kroh Andreas , Cramer Thorsten , Ticconi Fabio , Costa Ivan G. , Tacke Frank , Gassler Nikolaus , Trautwein Christian , Liedtke Christian
Published: November 2021

Cyclin E1 (CCNE1) is a regulatory subunit of Cyclin-dependent kinase 2 (CDK2) and is thought to control the transition of quiescent cells into cell cycle progression. Recently, we identified CCNE1 and CDK2 as key factors for the initiation of hepatocellular carcinoma (HCC). In the present study, we dissected the contributions of CCNE1 and CDK2 for HCC progression in mice and patients. Therefore, we generated genetically modified mice allowing inducible deletion of Ccne1 or Cdk2. After initiation of HCC, using the hepatocarcinogen diethylnitrosamine (DEN), we deleted Ccne1 or Cdk2 and subsequently analysed HCC progression. The relevance of CCNE1 or CDK2 for human HCC progression was investigated by in silico database analysis. Interventional deletion of Ccne1, but not of Cdk2, substantially reduced the HCC burden in mice. Ccne1-deficient HCCs were characterised by attenuated proliferation, impaired DNA damage response and downregulation of markers for stemness and microinvasion. Additionally, the tumour microenvironment of Ccne1-deficient mice showed a reduction in immune mediators, myeloid cells and cancer-associated fibroblasts. In sharp contrast, Cdk2 was dispensable for HCC progression in mice. In agreement with our mouse data, CCNE1 was overexpressed in HCC patients independent of risk factors, and associated with reduced disease-free survival, a common signature for enhanced chromosomal instability, proliferation, dedifferentiation and invasion. However, CDK2 lacked diagnostic or prognostic value in HCC patients. In summary, CCNE1 drives HCC progression in a CDK2-independent manner in mice and man. Therefore, interventional inactivation of CCNE1 represents a promising strategy the treatment of liver cancer.
Biological Significance and Targeting of the FGFR Axis in Cancer
Authors: Chioni Athina-Myrto , Grose Richard P.
Published: November 2021

The pleiotropic effects of fibroblast growth factors (FGFs), the widespread expression of all seven signalling FGF receptors (FGFRs) throughout the body, and the dramatic phenotypes shown by many FGF/R knockout mice, highlight the diversity, complexity and functional importance of FGFR signalling. The FGF/R axis is critical during normal tissue development, homeostasis and repair. Therefore, it is not surprising that substantial evidence also pinpoints the involvement of aberrant FGFR signalling in disease, including tumourigenesis. FGFR aberrations in cancer include mutations, gene fusions, and amplifications as well as corrupted autocrine/paracrine loops. Indeed, many clinical trials on cancer are focusing on targeting the FGF/FGFR axis, using selective FGFR inhibitors, nonselective FGFR tyrosine kinase inhibitors, ligand traps, and monoclonal antibodies and some have already been approved for the treatment of cancer patients. The heterogeneous tumour microenvironment and complexity of FGFR signalling may be some of the factors responsible for the resistance or poor response to therapy with FGFR axis-directed therapeutic agents. In the present review we will focus on the structure and function of FGF(R)s, their common irregularities in cancer and the therapeutic value of targeting their function in cancer.
Raman Imaging and Fluorescence Lifetime Imaging Microscopy for Diagnosis of Cancer State and Metabolic Monitoring
Authors: Becker Lucas , Janssen Nicole , Layland Shannon L. , Mürdter Thomas E. , Nies Anne T. , Schenke-Layland Katja , Marzi Julia
Published: November 2021

Hurdles for effective tumor therapy are delayed detection and limited effectiveness of systemic drug therapies by patient-specific multidrug resistance. Non-invasive bioimaging tools such as fluorescence lifetime imaging microscopy (FLIM) and Raman-microspectroscopy have evolved over the last decade, providing the potential to be translated into clinics for early-stage disease detection, in vitro drug screening, and drug efficacy studies in personalized medicine. Accessing tissue- and cell-specific spectral signatures, Raman microspectroscopy has emerged as a diagnostic tool to identify precancerous lesions, cancer stages, or cell malignancy. In vivo Raman measurements have been enabled by recent technological advances in Raman endoscopy and signal-enhancing setups such as coherent anti-stokes Raman spectroscopy or surface-enhanced Raman spectroscopy. FLIM enables in situ investigations of metabolic processes such as glycolysis, oxidative stress, or mitochondrial activity by using the autofluorescence of co-enzymes NADH and FAD, which are associated with intrinsic proteins as a direct measure of tumor metabolism, cell death stages and drug efficacy. The combination of non-invasive and molecular-sensitive in situ techniques and advanced 3D tumor models such as patient-derived organoids or microtumors allows the recapitulation of tumor physiology and metabolism in vitro and facilitates the screening for patient-individualized drug treatment options.
Enhancing Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer Patients with iCE, a Novel System for Automated Multi-Criterial Treatment Planning Including Beam Angle Optimization
Authors: Fjellanger Kristine , Hysing Liv Bolstad , Heijmen Ben J. M. , Pettersen Helge Egil Seime , Sandvik Inger Marie , Sulen Turid Husevåg , Breedveld Sebastiaan , Rossi Linda
Published: November 2021

In this study, the novel iCE radiotherapy treatment planning system (TPS) for automated multi-criterial planning with integrated beam angle optimization (BAO) was developed, and applied to optimize organ at risk (OAR) sparing and systematically investigate the impact of beam angles on radiotherapy dose in locally advanced non-small cell lung cancer (LA-NSCLC). iCE consists of an in-house, sophisticated multi-criterial optimizer with integrated BAO, coupled to a broadly used commercial TPS. The in-house optimizer performs fluence map optimization to automatically generate an intensity-modulated radiotherapy (IMRT) plan with optimal beam angles for each patient. The obtained angles and dose-volume histograms are then used to automatically generate the final deliverable plan with the commercial TPS. For the majority of 26 LA-NSCLC patients, iCE achieved improved heart and esophagus sparing compared to the manually created clinical plans, with significant reductions in the median heart Dmean (8.1 vs. 9.0 Gy, p = 0.02) and esophagus Dmean (18.5 vs. 20.3 Gy, p = 0.02), and reductions of up to 6.7 Gy and 5.8 Gy for individual patients. iCE was superior to automated planning using manually selected beam angles. Differences in the OAR doses of iCE plans with 6 beams compared to 4 and 8 beams were statistically significant overall, but highly patient-specific. In conclusion, automated planning with integrated BAO can further enhance and individualize radiotherapy for LA-NSCLC.
Diagnostic Performance of Ex Vivo Fluorescence Confocal Microscopy in the Assessment of Diagnostic Biopsies of the Prostate
Authors: Titze Ulf , Hansen Torsten , Brochhausen Christoph , Titze Barbara , Schulz Birte , Gunnemann Alfons , Rocco Bernardo , Sievert Karl-Dietrich
Published: November 2021

Background: Fluorescence confocal microscopy (FCM) is a novel micro-imaging technique providing optical sections of examined tissue. The method has been well established for the diagnosis of tumors in dermatological specimens. Methods: We compare intraoperative diagnoses of the real-time application of FCM in pre-therapeutic prostate biopsies (35 patients, total number of biopsy specimens: n = 438) with the findings of conventional histology. Results: Prostate carcinoma was reliably diagnosed in all patients. Depending on scan quality and experience of the examiner, smaller lesions of well differentiated carcinoma (ISUP1) could not be consistently differentiated from reactive changes. Furthermore, in some cases there was difficulty to distinguish ISUP grade 2 from ISUP grade 1 tumors. ISUP grades 3–5 were reliably detected in FCM. Conclusions: Despite some limitations, FCM seems to be an effective tool for the timely assessment of prostate biopsies enabling reliable diagnosis of prostate cancer in patients requiring therapy.
The Use of Oncolytic Viruses in the Treatment of Multiple Myeloma
Authors: Stewart Georgia , Chantry Andrew , Lawson Michelle
Published: November 2021

Multiple myeloma accounts for 1% of all new cancers worldwide. It is the second most common haematological malignancy and has a low five-year survival rate (53.2%). Myeloma remains an incurable disease and is caused by the growth of malignant plasma cells in the bone marrow. Current anti-myeloma therapies (conventional chemotherapies, immunomodulatory drugs i.e., thalidomide and its’ analogues, proteasome inhibitors, monoclonal antibodies, and radiotherapy) initially substantially debulk tumour burden, but after a period of remission ‘plateau phase’ disease invariably relapses due to tumour recrudescence from foci of minimal residual disease (MRD) and accumulating drug resistance. Therefore, there is a compelling clinical need for the development of novel treatment regimens to target MRD and effectively eliminate all remaining tumour cells. This review will discuss the potential use of oncolytic virus (OV) therapies in the treatment of myeloma. Specifically, it will focus on preclinical studies using DNA viruses (adenovirus (Ad), vaccinia virus (VV), myxoma virus (MYXV), and herpes simplex virus (HSV)), RNA viruses (reovirus (reo), coxsackie virus, measles virus (MV) and bovine viral diarrhoea virus (BVDV), and vesicular stomatitis virus (VSV)), and on four types of viruses (VV, reo, MV-NIS and VSV-IFNβ-NIS) that have been assessed clinically in a small number of myeloma patients.
Prostate-Specific Membrane Antigen in Anaplastic and Poorly Differentiated Thyroid Cancer—A New Diagnostic and Therapeutic Target?
Authors: Wächter Sabine , Di Fazio Pietro , Maurer Elisabeth , Manoharan Jerena , Keber Corinna , Pfestroff Andreas , Librizzi Damiano , Bartsch Detlef K. , Luster Markus , Eilsberger Friederike
Published: November 2021

Several studies have demonstrated an expression of the prostate-specific membrane antigen (PSMA) in the cancer-related neovasculature of thyroid malignancies. Due to the poor prognosis and limited therapeutic options for patients with anaplastic (ATC) and poorly differentiated (PDTC) thyroid carcinoma, the aim of our study was to investigate the theranostic approach of PSMA expression in these patients. The PSMA uptake on Gallium-68 (68Ga)-PSMA-positron emission tomography/computed tomography (PET/CT) and glucose uptake on F-18-Fluordeoxyglucose (18F-FDG)-PET/CTs were analysed in two ATC and six PDTC patients. The PSMA expression in corresponding patients’ tissue samples was detected by immunohistochemistry. In addition, various tissue sections from 22 ATC and six PDTC patients were examined concerning PSMA expression. 68Ga-PSMA-PET/CT showed heterogeneous PSMA expression among patients and lesions. Six of the eight analyzed patients (two ATC, four PDTC) showed increased glucose metabolism without increased PSMA uptake after PET/CT. In one patient (PDTC), 18F-FDG-PET/CT tracer uptake was positive and 68Ga-PSMA-PET/CT showed heterogeneous results. Another patient (PDTC) evidenced only PSMA-positive lesions and received two cycles of Lutetium-177 (177Lu)-PSMA therapy, which kept his disease stable for seven months. There was a correlation between immunohistochemical PSMA expression and uptake on 68Ga-PMSA-PET/CT in three of the examined patients. Twenty-seven of the analyzed 39 ATC and 13 of the analyzed 22 PDTC tissue sections showed a strong PSMA expression. Considering the rarity of PDTC and ATC, which is the reason for the small patient population we studied, the findings of this study confirm the high diagnostic sensitivity and superiority of 18F-FDG-PET/CT in comparison to 68Ga-PSMA-PET/CT in the diagnosis of ATC and PDTC. However, it can be suggested that 68Ga-PMSA-PET/CT can be considered as a beneficial adjunct to the well-established 18F-FDG-PET/CT for a few individual selected patients with ATC and PDTC to detect lesions not discovered by 18F-FDG-PET/CT and to determine patients’ eligibility for a radioligand therapy. Radiolabelled PSMA-ligands may, in the future, represent a theranostic approach with only minor side effects for a few individual selected patients with ATC and PDTC who need alternative treatment options in case of progression when established therapies are no longer effective. However, due to the small sample size of our collective, larger studies are needed to allow for a final evaluation on the significance of PSMA-targeted diagnostic and therapy for ATC and PDTC.
Role and Clinical Utility of Cancer/Testis Antigens in Head and Neck Squamous Cell Carcinoma
Authors: Wu Sharon Changshan , Münger Karl
Published: November 2021

Cancer/testis (CT) antigens exhibit selective expression predominantly in immunoprivileged tissues in non-pathological contexts but are aberrantly expressed in diverse cancers. Due to their expression pattern, they have historically been attractive targets for immunotherapies. A growing number of studies implicate CT antigens in almost all hallmarks of cancer, suggesting that they may act as cancer drivers. CT antigens are expressed in head and neck squamous cell carcinomas. However, their role in the pathogenesis of these cancers remains poorly studied. Given that CT antigens hold intriguing potential as therapeutic targets and as biomarkers for prognosis and that they can provide novel insights into oncogenic mechanisms, their further study in the context of head and squamous cell carcinoma is warranted.
Expression of the Chemokine Receptor CCR7 in the Normal Adrenal Gland and Adrenal Tumors and Its Correlation with Clinical Outcome in Adrenocortical Carcinoma
Authors: Fuss Carmina Teresa , Other Katharina , Heinze Britta , Landwehr Laura-Sophie , Wiegering Armin , Kalogirou Charis , Hahner Stefanie , Fassnacht Martin
Published: November 2021

Background: The chemokine receptor CCR7 is crucial for an intact immune function, but its expression is also associated with clinical outcome in several malignancies. No data exist on the expression of CCR7 in adrenocortical tumors. Methods: CCR7 expression was investigated by qRT-PCR and immunohistochemistry in 4 normal adrenal glands, 59 adrenocortical adenomas, and 181 adrenocortical carcinoma (ACC) samples. Results: CCR7 is highly expressed in the outer adrenocortical zones and medulla. Aldosterone-producing adenomas showed lower CCR7 protein levels (H-score 1.3 ± 1.0) compared to non-functioning (2.4 ± 0.5) and cortisol-producing adenomas (2.3 ± 0.6), whereas protein expression was variable in ACC (1.8 ± 0.8). In ACC, CCR7 protein expression was significantly higher in lymph node metastases (2.5 ± 0.5) compared to primary tumors (1.8±0.8) or distant metastases (2.0 ± 0.4; p < 0.01). mRNA levels of CCR7 were not significantly different between ACCs, normal adrenals, and adrenocortical adenomas. In contrast to other tumor entities, neither CCR7 protein nor mRNA expression significantly impacted patients’ survival. Conclusion: We show that CCR7 is expressed on mRNA and protein level across normal adrenals, benign adrenocortical tumors, as well as ACCs. Given that CCR7 did not influence survival in ACC, it is probably not involved in tumor progression, but it could play a role in adrenocortical homeostasis.
Triple-Negative Breast Cancer Histological Subtypes with a Favourable Prognosis
Authors: Cserni Gábor , Quinn Cecily M. , Foschini Maria Pia , Bianchi Simonetta , Callagy Grace , Chmielik Ewa , Decker Thomas , Fend Falko , Kovács Anikó , van Diest Paul J. , Ellis Ian O. , Rakha Emad , Tot Tibor ,   European Working Group for Breast Screening Pathology
Published: November 2021

Triple-negative breast cancers (TNBC), as a group of tumours, have a worse prognosis than stage-matched non-TNBC and lack the benefits of routinely available targeted therapy. However, TNBC is a heterogeneous group of neoplasms, which includes some special type carcinomas with a relatively indolent course. This review on behalf of the European Working Group for Breast Screening Pathology reviews the literature on the special histological types of BC that are reported to have a triple negative phenotype and indolent behaviour. These include adenoid cystic carcinoma of classical type, low-grade adenosquamous carcinoma, fibromatosis-like metaplastic carcinoma, low-grade mucoepidermoid carcinoma, secretory carcinoma, acinic cell carcinoma, and tall cell carcinoma with reversed polarity. The pathological and known molecular features as well as clinical data including treatment and prognosis of these special TNBC subtypes are summarised and it is concluded that many patients with these rare TNBC pure subtypes are unlikely to benefit from systemic chemotherapy. A consensus statement of the working group relating to the multidisciplinary approach and treatment of these rare tumour types concludes the review.
Kinase Inhibitors’ Effects on Innate Immunity in Solid Cancers
Authors: Peng Chunying , Rabold Katrin , Mulder Willem J. M. , Jaeger Martin , Netea-Maier Romana T.
Published: November 2021

Innate immune cells constitute a plastic and heterogeneous cell population of the tumor microenvironment. Because of their high tumor infiltration and close interaction with resident tumor cells, they are compelling targets for anti-cancer therapy through either ablation or functionally reprogramming. Kinase inhibitors (KIs) that target aberrant signaling pathways in tumor proliferation and angiogenesis have been shown to have additional immunological effects on myeloid cells that may contribute to a protective antitumor immune response. However, in patients with malignancies, these effects are poorly described, warranting meticulous research to identify KIs’ optimal immunomodulatory effect to support developing targeted and more effective immunotherapy. As many of these KIs are currently in clinical trials awaiting approval for the treatment of several types of solid cancer, we evaluate here the information on this drug class’s immunological effects and how such mechanisms can be harnessed to improve combined treatment regimens in cancer.
Pathogenic BRCA Variants as Biomarkers for Risk in Prostate Cancer
Authors: McNevin Ciara S. , Cadoo Karen , Baird Anne-Marie , Murchan Pierre , Sheils Orla , McDermott Ray , Finn Stephen
Published: November 2021

Studies have demonstrated that men with Prostate Cancer (PCa) harboring BRCA2/BRCA1 genetic aberrations, are more likely to have worse disease and a poorer prognosis. A mutation in BRCA2 is known to confer the highest risk of PCa for men (8.6 fold in men ≤65 years) making BRCA genes a conceivable genomic biomarker for risk in PCa. These genes have attracted a lot of research attention however their role in the clinical assessment and treatment of PCa remains complex. Multiple studies have been published examining the relationship between prostate cancer and BRCA mutations. Here BRCA mutations are explored specifically as a biomarker for risk in PCa. It is in this context, we examined the prognostic, clinical and therapeutic role of BRCA2/BRCA1 mutations across the evolution of PCa. The impact of the inclusion of BRCA genes on genetic screening will also be outlined.
Advantages and Challenges of Using ctDNA NGS to Assess the Presence of Minimal Residual Disease (MRD) in Solid Tumors
Authors: Larribère Lionel , Martens Uwe M.
Published: November 2021

The ability to detect minimal residual disease (MRD) after a curative-intent surgery or treatment is of paramount importance, because it offers the possibility to help guide the clinical decisions related adjuvant therapy. Thus, the earlier MRD is detected, the earlier potentially beneficial treatment can be proposed to patients who might need it. Liquid biopsies, and in particular the next-generation sequencing of circulating tumor DNA (ctDNA) in the blood, have been the focus of an increasing amount of research in the past years. The ctDNA detection at advanced cancer stages is practicable for several solid tumors, and complements molecular information on acquired therapy resistance. In the context of MRD, it is by definition more challenging to detect ctDNA, but it is technically achievable and provides information on treatment response and probability of relapse significantly earlier than standard imaging methods. The clinical benefit of implementing this new technique in the routine is being tested in interventional clinical trials at the moment. We propose here an update of the current use of ctDNA detection by NGS as a tool to assess the presence of MRD and improve adjuvant treatment of solid tumors. We also discuss the main limitations and medium-term perspectives of this process in the clinic.
Low-Dose Pesticides Alter Primary Human Bone Marrow Mesenchymal Stem/Stromal Cells through ALDH2 Inhibition
Authors: Foucault Amélie , Ravalet Noémie , Besombes Joevin , Picou Frédéric , Gallay Nathalie , Babin Laetitia , Bourgeais Jérôme , Hamard Sophie , Domenech Jorge , Loyer Pascal , Vallet Nicolas , Lejeune Julien , Gyan Emmanuel , Béné Marie C. , Vallette François , Olivier Christophe , Hérault Olivier
Published: November 2021

(1) Background: The impact of occupational exposure to high doses of pesticides on hematologic disorders is widely studied. Yet, lifelong exposure to low doses of pesticides, and more particularly their cocktail effect, although poorly known, could also participate to the development of such hematological diseases as myelodysplastic syndrome (MDS) in elderly patients. (2) Methods: In this study, a cocktail of seven pesticides frequently present in water and food (maneb, mancozeb, iprodione, imazalil, chlorpyrifos ethyl, diazinon and dimethoate), as determined by the European Food Safety Authority, were selected. Their in vitro effects at low-doses on primary BM-MSCs from healthy volunteers were examined. (3) Results: Exposure of normal BM-MSCs to pesticides for 21 days inhibited cell proliferation and promoted DNA damage and senescence. Concomitantly, these cells presented a decrease in aldehyde dehydrogenase 2 (ALDH2: mRNA, protein and enzymatic activity) and an increase in acetaldehyde levels. Pharmacological inhibition of ALDH2 with disulfiram recapitulated the alterations induced by exposure to low doses of pesticides. Moreover, BM-MSCs capacity to support primitive hematopoiesis was significantly altered. Similar biological abnormalities were found in primary BM-MSCs derived from MDS patients. (4) Conclusions: these results suggest that ALDH2 could participate in the pathophysiology of MDS in elderly people long exposed to low doses of pesticides.
Treatment of Advanced Basal Cell Carcinoma with Hedgehog Pathway Inhibitors: A Multidisciplinary Expert Meeting
Authors: De Giorgi Vincenzo , Scarfì Federica , Trane Luciana , Silvestri Flavia , Venturi Federico , Zuccaro Biancamaria , Spinelli Giuseppe , Scoccianti Silvia , De Rosa Francesco , Dika Emi , Longo Caterina
Published: November 2021

Despite recent progress and the publishing of several clinical guidelines on the management of advanced basal cell carcinoma, there is still no comprehensive set of clinical guidelines addressing the complexity inherent to the use of Hedgehog pathway inhibitors in the treatment of advanced basal cell carcinoma in real-world clinical practice. To develop practical and valuable tools that help specialists improve the clinical management of these patients, we sought the opinion of expert physicians with extensive knowledge and experience in the treatment of advanced basal cell carcinoma.
Comment on Kronenfeld et al. Clinical Outcomes for Primary and Radiation-Associated Angiosarcoma of the Breast with Multimodal Treatment: Long-Term Survival Is Achievable. Cancers 2021, 13, 3814
Authors: Notter Markus , Stutz Emanuel , Thomsen Andreas R. , Kollár Attila , Vaupel Peter
Published: November 2021

On 2 July 2021, Kronenfeld et al. [...]
Tumor Suppressive Circular RNA-102450: Development of a Novel Diagnostic Procedure for Lymph Node Metastasis from Oral Cancer
Authors: Ando Toshiaki , Kasamatsu Atsushi , Kawasaki Kohei , Hiroshima Kazuya , Fukushima Reo , Iyoda Manabu , Nakashima Dai , Endo-Sakamoto Yosuke , Uzawa Katsuhiro
Published: November 2021

Circular RNAs (circRNAs), which form as covalently closed loop structures, have several biological functions such as regulation of cellular behavior by adsorbing microRNAs. However, there is limited information of circRNAs in oral squamous cell carcinoma (OSCC). Here, we aimed to elucidate the roles of aberrantly expressed circRNAs in OSCC. CircRNA microarray showed that circRNA-102450 was down-regulated in OSCC cells. Clinical validation of circRNA-102450 was performed using highly sensitive droplet digital PCR in preoperative liquid biopsy samples from 30 OSCC patients. Interestingly, none of 16 studied patients with high circRNA-102450 had regional lymph node metastasis (RLNM), whereas 4 of 14 studied patients (28.5%) with low expression had pathologically proven RLNM. Overexpressed circRNA-102450 significantly inhibited the tumor metastatic properties of cell proliferation, migration, and invasion. Furthermore, circRNA-102450 directly bound to, and consequently down-regulated, miR-1178 in OSCC cells. Taken together, circRNA-102450 has a tumor suppressive effect via the circRNA-102450/miR-1178 axis and may be a novel potential marker of RLNM in OSCC patients.
Oncogenic KRAS Requires Complete Loss of BAP1 Function for Development of Murine Intrahepatic Cholangiocarcinoma
Authors: Marcus Rebecca , Ferri-Borgogno Sammy , Hosein Abdel , Foo Wai Chin , Ghosh Bidyut , Zhao Jun , Rajapakshe Kimal , Brugarolas James , Maitra Anirban , Gupta Sonal
Published: November 2021

Intrahepatic cholangiocarcinoma (ICC) is a primary biliary malignancy that harbors a dismal prognosis. Oncogenic mutations of KRAS and loss-of-function mutations of BRCA1-associated protein 1 (BAP1) have been identified as recurrent somatic alterations in ICC. However, an autochthonous genetically engineered mouse model of ICC that genocopies the co-occurrence of these mutations has never been developed. By crossing Albumin-Cre mice bearing conditional alleles of mutant Kras and/or floxed Bap1, Cre-mediated recombination within the liver was induced. Mice with hepatic expression of mutant KrasG12D alone (KA), bi-allelic loss of hepatic Bap1 (BhomoA), and heterozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhetKA) developed primary hepatocellular carcinoma (HCC), but no discernible ICC. In contrast, mice with homozygous loss of Bap1 in conjunction with mutant KrasG12D expression (BhomoKA) developed discrete foci of HCC and ICC. Further, the median survival of BhomoKA mice was significantly shorter at 24 weeks when compared to the median survival of ≥40 weeks in BhetKA mice and approximately 50 weeks in BhomoA and KA mice (p < 0.001). Microarray analysis performed on liver tissue from KA and BhomoKA mice identified differentially expressed genes in the setting of BAP1 loss and suggests that deregulation of ferroptosis might be one mechanism by which loss of BAP1 cooperates with oncogenic Ras in hepato-biliary carcinogenesis. Our autochthonous model provides an in vivo platform to further study this lethal class of neoplasm.
miR-125b Promotes Colorectal Cancer Migration and Invasion by Dual-Targeting CFTR and CGN
Authors: Zhang Xiaohui , Li Tingyu , Han Ya-Nan , Ge Minghui , Wang Pei , Sun Lina , Liu Hao , Cao Tianyu , Nie Yongzhan , Fan Daiming , Guo Hao , Wu Kaichun , Zhao Xiaodi , Lu Yuanyuan
Published: November 2021

Metastasis contributes to the poor prognosis of colorectal cancer, the causative factor of which is not fully understood. Previously, we found that miR-125b (Accession number: MIMAT0000423) contributed to cetuximab resistance in colorectal cancer (CRC). In this study, we identified a novel mechanism by which miR-125b enhances metastasis by targeting cystic fibrosis transmembrane conductance regulator (CFTR) and the tight junction-associated adaptor cingulin (CGN) in CRC. We found that miR-125b expression was upregulated in primary CRC tumors and metastatic sites compared with adjacent normal tissues. Overexpression of miR-125b in CRC cells enhanced migration capacity, while knockdown of miR-125b decreased migration and invasion. RNA-sequencing (RNA-seq) and dual-luciferase reporter assays identified CFTR and CGN as the target genes of miR-125b, and the inhibitory impact of CFTR and CGN on metastasis was further verified both in vitro and in vivo. Moreover, we found that miR-125b facilitated the epithelial-mesenchymal transition (EMT) process and the expression and secretion of urokinase plasminogen activator (uPA) by targeting CFTR and enhanced the Ras Homolog Family Member A (RhoA)/Rho Kinase (ROCK) pathway activity by targeting CGN. Together, these findings suggest miR-125b as a key functional molecule in CRC and a promising biomarker for the diagnosis and treatment of CRC.
Bio-Templating: An Emerging Synthetic Technique for Catalysts. A Review
Authors: Herrera-Beurnio M. Carmen , Hidalgo-Carrillo Jesús , López-Tenllado Francisco J. , Martin-Gómez Juan , Estévez Rafael C. , Urbano Francisco J. , Marinas Alberto
Published: November 2021

In the last few years, researchers have focused their attention on the synthesis of new catalyst structures based on or inspired by nature. Biotemplating involves the transfer of biological structures to inorganic materials through artificial mineralization processes. This approach offers the main advantage of allowing morphological control of the product, as a template with the desired morphology can be pre-determined, as long as it is found in nature. This way, natural evolution through millions of years can provide us with new synthetic pathways to develop some novel functional materials with advantageous properties, such as sophistication, miniaturization, hybridization, hierarchical organization, resistance, and adaptability to the required need. The field of application of these materials is very wide, covering nanomedicine, energy capture and storage, sensors, biocompatible materials, adsorbents, and catalysis. In the latter case, bio-inspired materials can be applied as catalysts requiring different types of active sites (i.e., redox, acidic, basic sites, or a combination of them) to a wide range of processes, including conventional thermal catalysis, photocatalysis, or electrocatalysis, among others. This review aims to cover current experimental studies in the field of biotemplating materials synthesis and their characterization, focusing on their application in heterogeneous catalysis.
TiO2–Zeolite Metal Composites for Photocatalytic Degradation of Organic Pollutants in Water
Authors: Diban Nazely , Pacuła Aleksandra , Kumakiri Izumi , Barquín Carmen , Rivero Maria J. , Urtiaga Ane , Ortiz Inmaculada
Published: November 2021

Immobilization of photocatalysts in porous materials is an approach to significantly minimize the hazards of manipulation and recovery of nanoparticles. Inorganic materials, such as zeolites, are proposed as promising materials for photocatalyst immobilization mainly due to their photochemical stability. In this work, a green synthesis method is proposed to combine TiO2-based photocatalysts with commercial ZY zeolite. Moreover, a preliminary analysis of their performance as photocatalysts for the abatement of organic pollutants in waters was performed. Our results show that the physical mixture of TiO2 and zeolite maintains photocatalytic activity. Meanwhile, composites fabricated by doping TiO2–zeolite Y materials with silver and palladium nanoparticles do not contribute to improving the photocatalytic activity beyond that of TiO2.
Helical Polycarbenes Bearing D-Prolinol Ester Pendants: An Efficient Catalyst for Asymmetric Michael Addition Reaction
Authors: Liu Na , Zhou Xinyue , Zhou Li , Wu Zongquan
Published: November 2021

A novel diazoacetate monomer (1) carrying tert-butyloxycarboryl (Boc) protected D-prolinol ester was designed and synthesized successfully. Molecular weight-controlled polymerization of 1 using the complex of π-allylPdCl coordinated Wei-phos (LR) ligand gives a series of helical polycarbenes (poly-1ms) with well-defined molecular weights (Mns) and low polydispersity (Mw/Mns). Removing the protecting Boc groups on the D-prolinol ester pendants leads to the formation of helical poly-1m-As, which showed high optical activity. Furthermore, the poly-1m-As showed high catalytic ability on asymmetric Michael addition reaction (up to 76% ee and 94/6 dr). Both the enantioselectivity and diastereoselectivity of the Michael addition reaction were increased comparing to D-prolinol as catalyst. Moreover, the helical polycarbene catalyst can be easily recovered and reused at least four times without significant loss of its enantioselectivity and diastereoselectivity.
Palladium-Nickel Electrocatalysts on Nitrogen-Doped Reduced Graphene Oxide Nanosheets for Direct Hydrazine/Hydrogen Peroxide Fuel Cells
Authors: Hosseini Mir Ghasem , Daneshvari-Esfahlan Vahid , Aghajani Hossein , Wolf Sigrid , Hacker Viktor
Published: November 2021

In the present work, nitrogen-doped reduced graphene oxide-supported (NrGO) bimetallic Pd–Ni nanoparticles (NPs), fabricated by means of the electrochemical reduction method, are investigated as an anode electrocatalyst in direct hydrazine–hydrogen peroxide fuel cells (DHzHPFCs). The surface and structural characterization of the synthesized catalyst affirm the uniform deposition of NPs on the distorted NrGO. The electrochemical studies indicate that the hydrazine oxidation current density on Pd–Ni/NrGO is 1.81 times higher than that of Pd/NrGO. The onset potential of hydrazine oxidation on the bimetallic catalyst is also slightly more negative, i.e., the catalyst activity and stability are improved by Ni incorporation into the Pd network. Moreover, the Pd–Ni/NrGO catalyst has a large electrochemical surface area, a low activation energy value and a low resistance of charge transfer. Finally, a systematic investigation of DHzHPFC with Pd–Ni/NrGO as an anode and Pt/C as a cathode is performed; the open circuit voltage of 1.80 V and a supreme power density of 216.71 mW cm−2 is obtained for the synthesized catalyst at 60 °C. These results show that the Pd–Ni/NrGO nanocatalyst has great potential to serve as an effective and stable catalyst with low Pd content for application in DHzHPFCs.
TiO2-HfN Radial Nano-Heterojunction: A Hot Carrier Photoanode for Sunlight-Driven Water-Splitting
Authors: Zeng Sheng , Muneshwar Triratna , Riddell Saralyn , Manuel Ajay Peter , Vahidzadeh Ehsan , Kisslinger Ryan , Kumar Pawan , Alam Kazi Mohammad Monirul , Kobryn Alexander E. , Gusarov Sergey , Cadien Kenneth C. , Shankar Karthik
Published: November 2021

The lack of active, stable, earth-abundant, and visible-light absorbing materials to replace plasmonic noble metals is a critical obstacle for researchers in developing highly efficient and cost-effective photocatalytic systems. Herein, a core–shell nanotube catalyst was fabricated consisting of atomic layer deposited HfN shell and anodic TiO2 support layer with full-visible regime photoactivity for photoelectrochemical water splitting. The HfN active layer has two unique characteristics: (1) A large bandgap between optical and acoustic phonon modes and (2) No electronic bandgap, which allows a large population of long life-time hot carriers, which are used to enhance the photoelectrochemical performance. The photocurrent density (≈2.5 mA·cm−2 at 1 V vs. Ag/AgCl) obtained in this study under AM 1.5G 1 Sun illumination is unprecedented, as it is superior to most existing plasmonic noble metal-decorated catalysts and surprisingly indicates a photocurrent response that extends to 730 nm. The result demonstrates the far-reaching application potential of replacing active HER/HOR noble metals such as Au, Ag, Pt, Pd, etc. with low-cost plasmonic ceramics.
Intra-Molecular Electrical Field Regulated Nonlinear Catalyst Charge Transfer in the Organic Conjugated Molecular System
Authors: Li Quanjiang , Chen Shenghui , Wang Li , Liu Yanli , He Di , Wang Meishan , Wang Jingang
Published: November 2021

The application of organic conjugated molecular systems to photocatalysis is based on the charge transition with different electronegative substituents and the electron–hole separation behavior of charge transfer under light excitation. In this work, the relationship between the intra-molecular electrical field and molecular second-order nonlinear optical properties is investigated theoretically by the sum-of-states (SOS) method. We use substituents with different electron affinity energy to construct internal electric fields with different properties in similar conjugated systems. The studies of these systems reveal the intra-molecular electric field strength and mode regulation of nonlinear optical coefficients and explain its physical mechanism. The intra-molecular charge recombination caused by the electrostatic potential multipole field of different substituents changes the transition behavior of one-photon, resulting in the enhancement of nonlinear optical properties (second-harmonic generation and sum-frequency coefficient) greater than 104.
Aging-Related Cellular, Structural and Functional Changes in the Lymph Nodes: A Significant Component of Immunosenescence? An Overview
Authors: Cakala-Jakimowicz Marta , Kolodziej-Wojnar Paulina , Puzianowska-Kuznicka Monika
Published: November 2021

Aging affects all tissues and organs. Aging of the immune system results in the severe disruption of its functions, leading to an increased susceptibility to infections, an increase in autoimmune disorders and cancer incidence, and a decreased response to vaccines. Lymph nodes are precisely organized structures of the peripheral lymphoid organs and are the key sites coordinating innate and long-term adaptive immune responses to external antigens and vaccines. They are also involved in immune tolerance. The aging of lymph nodes results in decreased cell transport to and within the nodes, a disturbance in the structure and organization of nodal zones, incorrect location of individual immune cell types and impaired intercellular interactions, as well as changes in the production of adequate amounts of chemokines and cytokines necessary for immune cell proliferation, survival and function, impaired naïve T- and B-cell homeostasis, and a diminished long-term humoral response. Understanding the causes of these stromal and lymphoid microenvironment changes in the lymph nodes that cause the aging-related dysfunction of the immune system can help to improve long-term immune responses and the effectiveness of vaccines in the elderly.