bluuebunny/crossref_metadata_2025 huggingface dataset:
An Analysis of Real-Time Measured Solar Radiation and Daylight and Its Energy Implications for Semi-Transparent Building-Integrated Photovoltaic Façades
Authors: Li Danny H. W. , Aghimien Emmanuel I. , Alshaibani Khalid
Published: February 2023

For analyzing cooling loads, day-lighting, and building-integrated photovoltaic (BIPV) systems, solar radiation and daylight illuminance data are required. However, these data are sparse. Furthermore, studies have shown that the energy potential of building-integrated photovoltaic (BIPV) systems for the entire building skin (BS) and unconventional orientations, such as east, west, and north need further exploration. Thus, this study presents findings from measured solar data and an energy analysis of semi-transparent BIPV. Firstly, solar radiation and daylight data measured from June 2019 to May 2020 in Hong Kong are presented. The analyzed solar-radiation data were used to determine the solar-energy potential of BIPV for BS and the four principal building orientations (i.e., N, E, S and W). With a simple analytical approach, the solar data’s building-energy implications for semi-transparent BIPV were assessed. The findings showed that the annual average horizontal global-, diffuse-, and direct-irradiance values were 291.8, 164.3, and 127.5 W/m2/day, respectively. Similarly, 120, 72, and 107 klux were obtained as the peak global, diffuse, and direct illuminance, respectively. Furthermore, the results show the potential of using BIPV on the entire BS in Hong Kong. It was also observed that a semi-transparent BIPV façade integrated with daylight-linked lighting controls could offer significant energy savings in electric lighting and cooling while also producing energy. In particular, BIPV façades with a large window-to-wall ratio (WWR) of 80% can provide an overall energy benefit of up to 7126 kWh.
Combining Artificial Neural Network and Seeker Optimization Algorithm for Predicting Compression Capacity of Concrete-Filled Steel Tube Columns
Authors: Hu Pan , Aghajanirefah Hamidreza , Anvari Arsalan , Nehdi Moncef
Published: February 2023

Accurate and reliable estimation of the axial compression capacity can assist engineers toward an efficient design of circular concrete-filled steel tube (CCFST) columns, which are gaining popularity in diverse structural applications. This study proposes a novel methodology based on computational intelligence for estimating the compression capacity of CCFST. Accordingly, a conventional artificial neural network (ANN) is hybridized with a metaheuristic algorithm called the seeker optimization algorithm (SOA). Utilizing information such as the column’s length, compressive strength of ultra-high-strength concrete, and the diameter, thickness, yield stress, and ultimate stress of the steel tube, the capacity of the column is predicted through non-linear calculations. In addition to the SOA, the future search algorithm (FSA) and social ski driver (SSD) are used as comparative benchmarks. The prediction results showed that the SOA-ANN can learn and predict the compression capacity pattern with high accuracy (relative error < 2.5% and correlation > 0.99). Also, this model outperformed both benchmark hybrids (i.e., FSA-ANN and SSD-ANN). Apart from accuracy, the configuration of the SOA-ANN is simpler owing to the smaller population recruited for the optimization task. An explicit formula for the proposed model is developed, which, owing to its observed efficiency, can be reliably applied to CCFST columns for the early estimation of the compression capacity.
BIM and Ontology-Based DfMA Framework for Prefabricated Component
Authors: Qi Bing , Costin Aaron
Published: February 2023

The integration of Design for Manufacture and Assembly (DfMA) into the design process of industrialized construction has the potential to reduce errors and changes occurring after the design has been finalized, ultimately improving overall productivity. Based on DfMA, the designers would need to consider whether their designs meet the architectural and performance requirements, as well as the manufacturing and assembly requirements from assembly and manufacturing technicians. However, some limitations present challenges for DfMA-oriented prefabricated design, such as lack of information interoperability, lack of conflict detection and management, and inefficient data processing and requirement checking. Thus, this research presents a novel BIM and ontology-based framework for DfMA of prefabricated and modular components. Various types of algorithms, plugins, and programming are also integrated to support the operation of the framework. The primary functions of this framework include: (1) collection of various stakeholder requirements in a standardized data format; (2) conflict detection and resolution between the design, manufacturing, and assembly requirements; and (3) automated compliance checking of whether the designed BIM models meet DfMA requirements. This research applies the framework on a prefabricated hotel project as a case study to validate the feasibility of the framework. Based on the results of a user experience survey, the developed framework shows promise for improving the DfMA process and stakeholder communication. Although a few limitations were encountered, such as the low computer operating speed and the limited ontology, the framework has been validated and shows great potential in advancing prefabricated component design applications
Experimental Investigation on the Strength and Microscopic Properties of Cement-Stabilized Aeolian Sand
Authors: Cui Qiang , Liu Guang , Zhang Zhenhua , Fang Yiqiu , Gu Xudong
Published: February 2023

Aeolian sand widely exists in the desert of western China. The reinforcement of aeolian sand is of considerable significance to the construction of transmission lines in the desert. In order to study the impact of different cement contents and moisture content on the performance of the cement-stabilized aeolian sand, 18 types of samples of aeolian sand with different water and cement contents were prepared. The confined and unconfined compression tests of the aeolian sand samples were conducted on the TSZ series automatic triaxial instrument. The microscopic observation methods and macroscopic strength tests were adopted to understand the cement-stabilized mechanism. The results of the triaxial test manifest that both the moisture content and the cement content affect the stress-strain behavior of the cement-stabilized aeolian sand. The cement-stabilized effect on aeolian sand can be estimated by the degree of hydration reaction. Microscopic test results show that as the cement content increases, the pores in the microstructure decrease, and some crystalline substances appear. The content of calcium silicate hydrate (C-S-H), which is one of the hydration products, is measured by the X-ray diffraction method. The results indicate that the solidification effect of cement is related to the C-S-H percentage. For 3% water content, the percentage of C-S-H goes up first with the increase of cement content and then gradually decreases at the cement content of 6%. When the water content goes up to 5% and 7%, it is found that the production of C-S-H gel increases with cement content.
Risk Stratification for Management of Solitary Fibrous Tumor/Hemangiopericytoma of the Central Nervous System
Authors: Kinslow Connor J. , Rae Ali I. , Kumar Prashanth , McKhann Guy M. , Sisti Michael B. , Bruce Jeffrey N. , Yu James B. , Cheng Simon K. , Wang Tony J. C.
Published: February 2023

Introduction: Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) of the central nervous system (CNS) is a rare meningeal tumor. Given the absence of prospective or randomized data, there are no standard indications for radiotherapy. Recently, the NRG Oncology and EORTC cooperative groups successfully accrued and completed the first prospective trials evaluating risk-adapted adjuvant radiotherapy strategies for meningiomas. Using a similar framework, we sought to develop prognostic risk categories that may predict the survival benefit associated with radiotherapy, using two large national datasets. Methods: We queried the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) databases for all newly diagnosed cases of SFT/HPC within the CNS. Risk categories were created, as follows: low risk—grade 1, with any extent of resection (EOR) and grade 2, with gross–total resection; intermediate risk—grade 2, with biopsy/subtotal resection; high risk—grade 3 with any EOR. The Kaplan–Meier method and Cox proportional hazards regressions were used to determine the association of risk categories with overall and cause-specific survival. We then determined the association of radiotherapy with overall survival in the NCDB, stratified by risk group. Results: We identified 866 and 683 patients from the NCDB and SEER databases who were evaluated, respectively. In the NCDB, the 75% survival times for low- (n = 312), intermediate- (n = 239), and high-risk (n = 315) patients were not reached, 86 months (HR 1.60 (95% CI 1.01–2.55)), and 55 months (HR 2.56 (95% CI 1.68–3.89)), respectively. Our risk categories were validated for overall and cause-specific survival in the SEER dataset. Radiotherapy was associated with improved survival in the high- (HR 0.46 (0.29–0.74)) and intermediate-risk groups (HR 0.52 (0.27–0.99)) but not in the low-risk group (HR 1.26 (0.60–2.65)). The association of radiotherapy with overall survival remained significant in the multivariable analysis for the high-risk group (HR 0.55 (0.34–0.89)) but not for the intermediate-risk group (HR 0.74 (0.38–1.47)). Similar results were observed in a time-dependent landmark sensitivity analysis. Conclusion: Risk stratification based on grade and EOR is prognostic of overall and cause-specific survival for SFT/HPCs of the CNS and performs better than any individual clinical factor. These risk categories appear to predict the survival benefit from radiotherapy, which is limited to the high-risk group and, potentially, the intermediate-risk group. These data may serve as the basis for a prospective study evaluating the management of meningeal SFT/HPCs.
P38 Mediates Tumor Suppression through Reduced Autophagy and Actin Cytoskeleton Changes in NRAS-Mutant Melanoma
Authors: Banik Ishani , Ghosh Adhideb , Beebe Erin , Burja Blaž , Frank Bertoncelj Mojca , Dooley Christopher , Markkanen Enni , Dummer Reinhard , Busch-Nentwich Elisabeth , Levesque Mitchell
Published: February 2023

Hotspot mutations in the NRAS gene are causative genetic events associated with the development of melanoma. Currently, there are no FDA-approved drugs directly targeting NRAS mutations. Previously, we showed that p38 acts as a tumor suppressor in vitro and in vivo with respect to NRAS-mutant melanoma. We observed that because of p38 activation through treatment with the protein synthesis inhibitor, anisomycin leads to a transient upregulation of several targets of the cAMP pathway, representing a stressed cancer cell state that is often observed by therapeutic doses of MAPK inhibitors in melanoma patients. Meanwhile, genetically induced p38 or its stable transduction leads to a distinct cellular transcriptional state. Contrary to previous work showing an association of invasiveness with high p38 levels in BRAF-mutated melanoma, there was no correlation of p38 expression with NRAS-mutant melanoma invasion, highlighting the difference in BRAF and NRAS-driven melanomas. Although the role of p38 has been reported to be that of both tumor suppressor and oncogene, we show here that p38 specifically plays the role of a tumor suppressor in NRAS-mutant melanoma. Both the transient and stable activation of p38 elicits phosphorylation of mTOR, reported to be a master switch in regulating autophagy. Indeed, we observed a correlation between elevated levels of phosphorylated mTOR and a reduction in LC3 conversion (LCII/LCI), indicative of suppressed autophagy. Furthermore, a reduction in actin intensity in p38–high cells strongly suggests a role of mTOR in regulating actin and a remodeling in the NRAS-mutant melanoma cells. Therefore, p38 plays a tumor suppressive role in NRAS-mutant melanomas at least partially through the mechanism of mTOR upregulation, suppressed autophagy, and reduced actin polymerization. One or more combinations of MEK inhibitors with either anisomycin, rapamycin, chloroquine/bafilomycin, and cytochalasin modulate p38 activation, mTOR phosphorylation, autophagy, and actin polymerization, respectively, and they may provide an alternate route to targeting NRAS-mutant melanoma.
PIEZO1-Related Physiological and Pathological Processes in CNS: Focus on the Gliomas
Authors: Hong Rui , Yang Dianxu , Jing Yao , Chen Shiwen , Tian Hengli , Yang Yang
Published: February 2023

PIEZO1 is ubiquitously expressed in cells in different kinds of tissues throughout the body, which can sense physical or mechanical stimuli and translate them into intracellular electrochemical signals to regulate organism functions. In particular, PIEZO1 appears in complex interactive regulatory networks as a central node, governing normal and pathological functions in the body. However, the effect and mechanism of the activation or expression of PIEZO1 in diseases of the central nervous system (CNS) remain unclear. On one hand, in CNS diseases, pathophysiological processes in neurons and glial are often accompanied by variations in the mechanical properties of the cellular and extracellular matrix stiffness. The expression of PIEZO1 can therefore be upregulated, in responding to mechanical stimulation, to drive the biological process in cells, which in turns indirectly affects the cellular microenvironment, resulting in alterations of the cellular status. On the other hand, it may have contradictory effects with the change of active patterns and/or subcellular location. This review highlights the biological processes involved with PIEZO1 in CNS cells, with special emphasis on its multiple roles in glioma-associated phenotypes. In conclusion, PIEZO1 can be used as an indicator to assess the malignancy and prognosis of patients with gliomas, as well as a therapeutic target for clinical application following fully exploring the potential mechanism of PIEZO1 in CNS diseases.
Elevation of Cytoplasmic Calcium Suppresses Microtentacle Formation and Function in Breast Tumor Cells
Authors: Chang Katarina T. , Thompson Keyata N. , Pratt Stephen J. P. , Ju Julia A. , Lee Rachel M. , Mathias Trevor J. , Mull Makenzy L. , Annis David A. , Ory Eleanor C. , Stemberger Megan B. , Vitolo Michele I. , Martin Stuart S.
Published: February 2023

Cytoskeletal remodeling in circulating tumor cells (CTCs) facilitates metastatic spread. Previous oncology studies examine sustained aberrant calcium (Ca2+) signaling and cytoskeletal remodeling scrutinizing long-term phenotypes such as tumorigenesis and metastasis. The significance of acute Ca2+ signaling in tumor cells that occur within seconds to minutes is overlooked. This study investigates rapid cytoplasmic Ca2+ elevation in suspended cells on actin and tubulin cytoskeletal rearrangements and the metastatic microtentacle (McTN) phenotype. The compounds Ionomycin and Thapsigargin acutely increase cytoplasmic Ca2+, suppressing McTNs in the metastatic breast cancer cell lines MDA-MB-231 and MDA-MB-436. Functional decreases in McTN-mediated reattachment and cell clustering during the first 24 h of treatment are not attributed to cytotoxicity. Rapid cytoplasmic Ca2+ elevation was correlated to Ca2+-induced actin cortex contraction and rearrangement via myosin light chain 2 and cofilin activity, while the inhibition of actin polymerization with Latrunculin A reversed Ca2+-mediated McTN suppression. Preclinical and phase 1 and 2 clinical trial data have established Thapsigargin derivatives as cytotoxic anticancer agents. The results from this study suggest an alternative molecular mechanism by which these compounds act, and proof-of-principle Ca2+-modulating compounds can rapidly induce morphological changes in free-floating tumor cells to reduce metastatic phenotypes.
Hyperparameter Optimizer with Deep Learning-Based Decision-Support Systems for Histopathological Breast Cancer Diagnosis
Authors: Obayya Marwa , Maashi Mashael S. , Nemri Nadhem , Mohsen Heba , Motwakel Abdelwahed , Osman Azza Elneil , Alneil Amani A. , Alsaid Mohamed Ibrahim
Published: February 2023

Histopathological images are commonly used imaging modalities for breast cancer. As manual analysis of histopathological images is difficult, automated tools utilizing artificial intelligence (AI) and deep learning (DL) methods should be modelled. The recent advancements in DL approaches will be helpful in establishing maximal image classification performance in numerous application zones. This study develops an arithmetic optimization algorithm with deep-learning-based histopathological breast cancer classification (AOADL-HBCC) technique for healthcare decision making. The AOADL-HBCC technique employs noise removal based on median filtering (MF) and a contrast enhancement process. In addition, the presented AOADL-HBCC technique applies an AOA with a SqueezeNet model to derive feature vectors. Finally, a deep belief network (DBN) classifier with an Adamax hyperparameter optimizer is applied for the breast cancer classification process. In order to exhibit the enhanced breast cancer classification results of the AOADL-HBCC methodology, this comparative study states that the AOADL-HBCC technique displays better performance than other recent methodologies, with a maximum accuracy of 96.77%.
Impact of Immune-Related Adverse Events on Immune Checkpoint Inhibitors Treated Cancer Patients’ Survival: Single Center Experience and Literature Review
Authors: Romão Raquel , Mendes Ana S. , Ranchor Ridhi , Ramos Maria João , Coelho João , Pichel Rita Carrilho , Azevedo Sérgio Xavier , Fidalgo Paula , Araújo António
Published: February 2023

Immune-related adverse events have emerged as a new challenge and its correlation with survival remains unclear. The goal of our study was to investigate the effect of irAE on survival outcomes in solid tumor patients receiving ICI treatment. This was a retrospective, single-center study at a university hospital involving patients with malignancy who received immune checkpoint inhibitors. Chart review was performed on each patient, noting any irAE, including new events or worsening of previous autoimmune condition after starting treatment with ICI. A total of 155 patients were included, 118 (76.1%) were male, with median age of 64 years. Median follow up time was 36 months. Seventy patients (45.2%) had at least one irAE. Of all irAE, nine (8.1%) were classified as grade 3 or higher according to the CTCAE version 5.0. There was one death secondary to pneumonitis. Median ICI cycles until first irAE onset was 4 (range: 2–99). The objective response rate was higher for patients who developed irAE (18.7% vs. 9.0%; p = 0.001), as was median overall survival (18 months (95% CI, 8.67–27.32) vs. 10 (95% CI, 3.48–16.52) months; p < 0.016) and progression free survival (10 months (95% CI, 5.44–14.56) vs. 3 months (95% CI, 1.94–4.05); p = 0.000). The risk of death in patients with irAE was 33% lower when compared to patients without such events (hazard ratio (HR): 0.67; 95% CI, 0.46–0.99; p = 0.043). Development of irAE predicted better outcomes, including OS in patients with advanced solid tumors treated with ICI. Further prospective studies are needed to explore and validate this prognostic value.
Early Onset Colorectal Cancer in Arabs, Are We Dealing with a Distinct Disease?
Authors: Al Zaabi Adhari , Al Shehhi Asmaa , Sayed Shaymaa , Al Adawi Humaid , Al Faris Faris , Al Alyani Omaima , Al Asmi Maitha , Al-Mirza Abdulrahman , Panchatcharam Sathiya , Al-Shaibi Maha
Published: February 2023

Early-onset colorectal cancer (EOCRC) incidence is increasing worldwide. Efforts are directed to understand the biological and clinical signatures of EOCRC compared to late-onset colorectal cancer (LOCRC). EOCRC is thought to present differently across different ethnic groups and geographical regions. This study was an attempt to contribute with data from the Arab world toward the understanding of the clinicopathological parameters of EOCRC compared to LOCRC. Data from 254 CRC patients diagnosed at Sultan Qaboos University Hospital from the period 2015–2020 were studied. About 32.6% of all diagnosed CRC patients are below 50 years old, with no differences in gender distribution between EOCRC and LOCRC (p-value 0.417). Rectal involvement and tumor laterality were comparable among the two groups. Adenocarcinoma accounts for 83.3% and 94.2% of EOCRC and LOCRC, respectively. More mucinous and signet ring adenocarcinoma (8.3% each) were reported in EOCRC than LOCRC (2.9% and 2.2%, respectively). MLH1 and PMS2 loss are more common among LOCRC, but MSH6 loss is more frequent in EOCRC. The overall survival of EOCRC and LOCRC was comparable (median survival 64.88 and 67.24 months, respectively). This study showed comparable clinicopathological parameters between EOCRC and LOCRC from Arabs, which adds to the bigger picture of understand the disease.
Systematic Evaluation of Antigenic Stimulation in Chronic Lymphocytic Leukemia: Humoral Immunity as Biomarkers for Disease Evolution
Authors: Landeira-Viñuela Alicia , Alcoceba-Sanchez Miguel , Navarro-Bailón Almudena , Arias-Hidalgo Carlota , Juanes-Velasco Pablo , Sánchez-Santos José Manuel , Lecrevisse Quentin , Pedreira Carlos Eduardo , García-Vaquero Marina L. , Hernández Ángela-Patricia , Montalvillo Enrique , Góngora Rafael , De las Rivas Javier , González-Díaz Marcos , Orfao Alberto , Fuentes Manuel
Published: February 2023

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Studies of CLL antibody reactivity have shown differential targets to autoantigens and antimicrobial molecular motifs that support the current hypothesis of CLL pathogenesis. Methods: In this study, we conducted a quantitative serum analysis of 7 immunoglobulins in CLL and monoclonal B-cell lymphocytosis (MBL) patients (bead-suspension protein arrays) and a serological profile (IgG and IgM) study of autoantibodies and antimicrobial antigens (protein microarrays). Results: Significant differences in the IgA levels were observed according to disease progression and evolution as well as significant alterations in IgG1 according to IGHV mutational status. More representative IgG autoantibodies in the cohort were against nonmutagenic proteins and IgM autoantibodies were against vesicle proteins. Antimicrobial IgG and IgM were detected against microbes associated with respiratory tract infections. Conclusions: Quantitative differences in immunoglobulin serum levels could be potential biomarkers for disease progression. In the top 5 tumoral antigens, we detected autoantibodies (IgM and IgG) against proteins related to cell homeostasis and metabolism in the studied cohort. The top 5 microbial antigens were associated with respiratory and gastrointestinal infections; moreover, the subsets with better prognostics were characterized by a reactivation of Cytomegalovirus. The viral humoral response could be a potential prognosis biomarker for disease progression.
Response to Ovarian Stimulation for Urgent Fertility Preservation before Gonadotoxic Treatment in BRCA-Pathogenic-Variant-Positive Breast Cancer Patients
Authors: El Moujahed Lina , Philis Robin , Grynberg Michael , Laot Lucie , Mur Pauline , Amsellem Noemi , Mayeur Anne , Benoit Alexandra , Rakrouki Sophia , Sifer Christophe , Peigné Maeliss , Sonigo Charlotte
Published: February 2023

BRCA 1/2 pathogenic variants increase the risk of developing early and aggressive breast cancers (BC). For these patients, fertility potential can be directly affected by oncologic treatments. In addition, evidence indicates that BRCA-mutated women had a significant reduction in their ovarian reserve. In order to improve their chances of conception after the completion of cancer treatments, fertility preservation should be proposed before the administration of gonadotoxic drugs, ideally by oocyte vitrification after controlled ovarian hyperstimulation (COH). The present investigation aims to assess the ovarian response to COH in BRCA 1/2-pathogenic-variant carriers diagnosed with BC. Patient characteristics and COH outcomes were compared between BRCA-positive (n = 54) and BRCA-negative (n = 254) patients. The number of oocytes recovered did not differ between the two groups. However, the oocyte maturation rate and the number of mature oocytes obtained (7 (4.5–11.5) vs. 9 (5–14) oocytes, p = 0.05) were significantly lower in the BRCA-mutated patients. Although individualized COH protocols should be discussed, BRCA-mutated patients would benefit from FP before BC occurs, in order to cope with the potential accelerated decline of their ovarian reserve, optimize the success rate of FP by repeating COH cycles, and to preserve the feasibility of PGT-M by collecting a large amount of eggs.
Primary Tumor Resection for Metastatic Colorectal, Gastric and Pancreatic Cancer Patients: In Search of Scientific Evidence to Inform Clinical Practice
Authors: Fanotto Valentina , Salani Francesca , Vivaldi Caterina , Scartozzi Mario , Ribero Dario , Puzzoni Marco , Montagnani Francesco , Leone Francesco , Vasile Enrico , Bencivenga Maria , De Manzoni Giovanni , Basile Debora , Fornaro Lorenzo , Masi Gianluca , Aprile Giuseppe
Published: February 2023

The management of the primary tumor in metastatic colorectal, gastric and pancreatic cancer patients may be challenging. Indeed, primary tumor progression could be associated with severe symptoms, compromising the quality of life and the feasibility of effective systemic therapy, and might result in life-threatening complications. While retrospective series have suggested that surgery on the primary tumor may confer a survival advantage even in asymptomatic patients, randomized trials seem not to definitively support this hypothesis. We discuss the evidence for and against primary tumor resection for patients with metastatic gastrointestinal (colorectal, gastric and pancreatic) cancers treated with systemic therapies and put in context the pros and cons of the onco-surgical approach in the time of precision oncology. We also evaluate current ongoing trials on this topic, anticipating how these will influence both research and everyday practice.
Combination Modality Using Quercetin to Enhance the Efficacy of Docetaxel in Prostate Cancer Cells
Authors: Sharma Satish , Cwiklinski Katherine , Mahajan Supriya D. , Schwartz Stanley A. , Aalinkeel Ravikumar
Published: February 2023

The standard of care chemotherapy drug presently used to treat castration-resistant prostate cancer (CRPC), docetaxel (Doc), also develops chemoresistance, thereby reducing its clinical utility. Since resistance to chemotherapy drugs can be overcome by co-treatment with plant-based bio-active compounds we undertook the present study to evaluate if quercetin (Que), a flavonoid present in plants such as onions, apples, olives, and grapes can enhance the efficacy of Doc. We studied the separate and combined effects of Que and Doc at different doses and different combination approaches in two different prostate cancer cell lines, DU-145 (moderately aggressive) and PC-3 (very aggressive), and assessed the effects of these combinations on viability, proliferation, and apoptosis. Monotherapy with these drugs showed dose-dependent cytotoxicity; however, only Doc monotherapy showed a statistically significant difference in IC50 levels (IC50 = 4.05 ± 0.52 nM for PC-3 and IC50 = 2.26 ± 0.22 nM for DU-145). In combination treatment, we used three different treatment approaches (TAP). The concentrations and range analyzed were chosen based on the approximate cytotoxicity of 30–50% when the drugs were used individually. Our observations indicate that the most beneficial effect of the Que and Doc combination was obtained with the TAP-2 approach, which is pre-treatment with all doses of Que for 24 h followed by low doses of Doc for another 24 h. Using this approach, we observed synergism at low concentrations of Doc (0.5 and 1.0 nM) and all concentrations of Que. An additive effect was observed at moderate and high concentrations of Doc (1.5, 2.0, and 2.5 nM) and all concentrations of Que in both cell lines. The TAP-2 strategy was also helpful in overcoming Doc resistance in resistant CaP cells. In summary, Que improved the therapeutic effect of Doc in CRPC, and it is proposed that this improvement is mediated through multiple mechanisms. This study provides a novel therapeutic modality for an effective combination using Doc and Que to enhance the efficacy of Doc in an innocuous manner for Doc resistance and CRPC treatment.
SAINT: A Phase I/Expanded Phase II Study Using Safe Amounts of Ipilimumab, Nivolumab and Trabectedin as First-Line Treatment of Advanced Soft Tissue Sarcoma
Authors: Gordon Erlinda Maria , Chawla Sant P. , Tellez Walter Andree , Younesi Elan , Thomas Sonu , Chua-Alcala Victoria S. , Chomoyan Hripsime , Valencia Chrysler , Brigham Don Arlen , Moradkhani Ania , Quon Doris , Srikureja Amornchit , Wong Steven G. , Tseng William , Federman Noah
Published: February 2023

Background: This Phase 1/2 study is based on the hypothesis that immune checkpoint inhibitors are more effective when given earlier in the course of the disease for advanced soft tissue sarcoma. Methods: Phase I endpoints—maximum tolerated dose in previously treated patients; Phase II endpoints—best response, progression free survival and overall survival and incidence of adverse events in previously untreated patients; Phase I treatments—escalating doses of trabectedin (1.0, 1.2, 1.5 mg/m2) as continuous intravenous infusion over 24 h every 3 weeks, 1 mg/kg of ipilimumab given intravenously every 12 weeks, and 3 mg/kg of nivolumab given intravenously every 2 weeks; Phase II treatments—maximum tolerated dose of trabectedin and defined doses of ipilimumab and nivolumab. Results: Phase I (n = 9)—the maximum tolerated dose of trabectedin was 1.2 mg/m2; Phase II (n = 79)—6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median progression-free survival, 6.7 months (CI 95%: 4.4–7.9), median overall survival, 24.6 months (CI 95%: 17.0–.); Grade 3/4 therapy-related adverse events (n = 92)—increased ALT (25%), fatigue (8.7%), increased AST (8.7%), decreased neutrophil count (5.4%) and anemia (4.6%). Conclusion: SAINT is a safe and effective first-line treatment for advanced soft tissue sarcoma.
Patterns of Somatic Variants in Colorectal Adenoma and Carcinoma Tissue and Matched Plasma Samples from the Hungarian Oncogenome Program
Authors: Kalmár Alexandra , Galamb Orsolya , Szabó Gitta , Pipek Orsolya , Medgyes-Horváth Anna , Barták Barbara K. , Nagy Zsófia B. , Szigeti Krisztina A. , Zsigrai Sára , Csabai István , Igaz Péter , Molnár Béla , Takács István
Published: February 2023

Analysis of circulating cell-free DNA (cfDNA) of colorectal adenoma (AD) and cancer (CRC) patients provides a minimally invasive approach that is able to explore genetic alterations. It is unknown whether there are specific genetic variants that could explain the high prevalence of CRC in Hungary. Whole-exome sequencing (WES) was performed on colon tissues (27 AD, 51 CRC) and matched cfDNAs (17 AD, 33 CRC); furthermore, targeted panel sequencing was performed on a subset of cfDNA samples. The most frequently mutated genes were APC, KRAS, and FBN3 in AD, while APC, TP53, TTN, and KRAS were the most frequently mutated in CRC tissue. Variants in KRAS codons 12 (AD: 8/27, CRC: 11/51 (0.216)) and 13 (CRC: 3/51 (0.06)) were the most frequent in our sample set, with G12V (5/27) dominance in ADs and G12D (5/51 (0.098)) in CRCs. In terms of the cfDNA WES results, tumor somatic variants were found in 6/33 of CRC cases. Panel sequencing revealed somatic variants in 8 out of the 12 enrolled patients, identifying 12/20 tumor somatic variants falling on its targeted regions, while WES recovered only 20% in the respective regions in cfDNA of the same patients. In liquid biopsy analyses, WES is less efficient compared to the targeted panel sequencing with a higher coverage depth that can hold a relevant clinical potential to be applied in everyday practice in the future.
Maternal Cancer and Perception of Child Psychological Adjustment: The Role of Mother’s Anxiety, Depression, and Parenting Stress
Authors: Babore Alessandra , Trumello Carmen , Brandão Tânia , Cavallo Alessandra , Bramanti Sonia Monique
Published: February 2023

A mother’s cancer diagnosis may have consequences for all family members, particularly for children, since it makes a parent less physically and emotionally available, with effects on the relationship with the child and his/her development. The main aim of this study was to analyze children’s psychological adjustment in the context of maternal cancer by considering factors related to the child (i.e., age and sex), the mother (psychological adjustment), and cancer (i.e., time elapsed from the diagnosis and current oncological treatment). Self-report questionnaires investigating mothers’ parenting stress, depression, anxiety, and children’s emotional and behavioral problems were administered to 124 mothers (mean age = 44.52 years; SD = 7.22) diagnosed with cancer. A hierarchical regression analysis highlighted that time since diagnosis and mothers’ anxiety and parenting stress accounted for almost 44% of the variance of the children’s difficulties. Maternal depression, current oncological treatment, and the child’s age and sex were not statistically significant. Higher mothers’ parenting stress and anxiety and a longer time elapsed since the first diagnosis predicted higher levels of children’s emotional and behavioral problems. These findings highlight the need to identify precursors of childhood distress in the context of maternal cancer and to develop structured programs to support both mothers and children.
Immune Checkpoint Receptor/Ligand Expression and Chemotherapy in Colorectal Cancer
Authors: Benelli Roberto , Zocchi Maria Raffaella , Poggi Alessandro
Published: February 2023

Immune checkpoint (IC) molecules act as receptors, expressed on immune effector cells, that are able to recognize specific ligands in normal or tumor cells [...]
The Pleiotropic Effects of Gut Microbiota in Colorectal Cancer Progression: How to Turn Foes into Friends
Authors: Tardito Samuele , Matis Serena , Benelli Roberto
Published: February 2023

Colorectal Cancer (CRC) is one of most frequent malignant cancers, showing high lethality worldwide [...]
Vemurafenib and Dabrafenib Downregulates RIPK4 Level
Authors: Madej Ewelina , Brożyna Anna A. , Adamczyk Agnieszka , Wronski Norbert , Harazin-Lechowska Agnieszka , Muzyk Anna , Makuch Krzysztof , Markiewicz Michal , Rys Janusz , Wolnicka-Glubisz Agnieszka
Published: February 2023

Vemurafenib and dabrafenib are BRAF kinase inhibitors (BRAFi) used for the treatment of patients with melanoma carrying the V600E BRAF mutation. However, melanoma cells develop resistance to both drugs when used as monotherapy. Therefore, mechanisms of drug resistance are investigated, and new molecular targets are sought that could completely inhibit melanoma progression. Since receptor-interacting protein kinase (RIPK4) probably functions as an oncogene in melanoma and its structure is similar to the BRAF protein, we analyzed the impact of vemurafenib and dabrafenib on RIPK4 in melanomas. The in silico study confirmed the high similarity of BRAF kinase domains to the RIPK4 protein at both the sequence and structural levels and suggests that BRAFi could directly bind to RIPK4 even more strongly than to ATP. Furthermore, BRAFi inhibited ERK1/2 activity and lowered RIPK4 protein levels in BRAF-mutated melanoma cells (A375 and WM266.4), while in wild-type BRAF cells (BLM and LoVo), both inhibitors decreased the level of RIPK4 and enhanced ERK1/2 activity. The phosphorylation of phosphatidylethanolamine binding protein 1 (PEBP1)—a suppressor of the BRAF/MEK/ERK pathway—via RIPK4 observed in pancreatic cancer did not occur in melanoma. Neither downregulation nor upregulation of RIPK4 in BRAF- mutated cells affected PEBP1 levels or the BRAF/MEK/ERK pathway. The downregulation of RIPK4 inhibited cell proliferation and the FAK/AKT pathway, and increased BRAFi efficiency in WM266.4 cells. However, the silencing of RIPK4 did not induce apoptosis or necroptosis. Our study suggests that RIPK4 may be an off-target for BRAF inhibitors.
Immune-Activated B Cells Are Dominant in Prostate Cancer
Authors: Saudi Aws , Banday Viqar , Zirakzadeh A. Ali , Selinger Martin , Forsberg Jon , Holmbom Martin , Henriksson Johan , Waldén Mauritz , Alamdari Farhood , Aljabery Firas , Winqvist Ola , Sherif Amir
Published: February 2023

B cells are multifaceted immune cells responding robustly during immune surveillance against tumor antigens by presentation to T cells and switched immunoglobulin production. However, B cells are unstudied in prostate cancer (PCa). We used flow cytometry to analyze B-cell subpopulations in peripheral blood and lymph nodes from intermediate–high risk PCa patients. B-cell subpopulations were related to clinicopathological factors. B-cell-receptor single-cell sequencing and VDJ analysis identified clonal B-cell expansion in blood and lymph nodes. Pathological staging was pT2 in 16%, pT3a in 48%, and pT3b in 36%. Lymph node metastases occurred in 5/25 patients (20%). Compared to healthy donors, the peripheral blood CD19+ B-cell compartment was significantly decreased in PCa patients and dominated by naïve B cells. The nodal B-cell compartment had significantly increased fractions of CD19+ B cells and switched memory B cells. Plasmablasts were observed in tumor-draining sentinel lymph nodes (SNs). VDJ analysis revealed clonal expansion in lymph nodes. Thus, activated B cells are increased in SNs from PCa patients. The increased fraction of switched memory cells and plasmablasts together with the presence of clonally expanded B cells indicate tumor-specific T-cell-dependent responses from B cells, supporting an important role for B cells in the protection against tumors.
Targeted-Lymphoma Drug Delivery System Based on the Sgc8-c Aptamer
Authors: Sicco Estefanía , Cerecetto Hugo , Calzada Victoria , Moreno María
Published: February 2023

Aptamers are emerging as a promising new class of functional nucleic acids because they can specifically bind to any target with high affinity and be easily modified chemically with different pharmacophoric subunits for therapy. The truncated aptamer, Sgc8-c, binds to tyrosine-protein kinase-like 7 receptor, a promising cancer therapeutic target, allowing the recognition of haemato-oncological malignancies, among others. We have previously developed aptamer-drug conjugates by chemical synthesis, hybridizing Sgc8-c and dasatinib, a drug proposed for lymphoma chemotherapy. One of the best-characterised Sgc8-c-dasatinib hybrids, namely Sgc8-c-carb-da, was capable of releasing dasatinib at an endosomal-pH. Herein, we probed the therapeutic potential of this aptamer-drug conjugate. Sgc8-c-carb-da specifically inhibited murine A20 B lymphocyte growth and produced cell death, mainly by late apoptosis and necrosis. In addition, Sgc8-c-carb-da generated an arrest in cell proliferation, with a cell cycle arrest in the Sub-G1-peak. The mitochondrial potential was altered accordingly to these pathways. Moreover, using an in vitro cell-targeting assay that mimics in vivo conditions, we showed that Sgc8-c-carb-da displayed higher (2.5-fold) cytotoxic effects than dasatinib. These findings provide proof-of-concept of the therapeutic value of Sgc8-c-carb-da for lymphoma, creating new opportunities for the chemical synthesis of targeted biotherapeutics.
Management of Recurrent Well-Differentiated Thyroid Carcinoma in the Neck: A Comprehensive Review
Authors: Cavalheiro Beatriz G. , Shah Jatin P. , Randolph Gregory W. , Medina Jesus E. , Tufano Ralph P. , Zafereo Mark , Hartl Dana M. , Nixon Iain J. , Guntinas-Lichius Orlando , Vander Poorten Vincent , López Fernando , Khafif Avi Hefetz , Owen Randall P. , Shaha Ashok , Rodrigo Juan P. , Rinaldo Alessandra , Mäkitie Antti A. , Silver Carl E. , Sanabria Alvaro , Kowalski Luiz P. , Ferlito Alfio
Published: February 2023

Surgery has been historically the preferred primary treatment for patients with well-differentiated thyroid carcinoma and for selected locoregional recurrences. Adjuvant therapy with radioactive iodine is typically recommended for patients with an intermediate to high risk of recurrence. Despite these treatments, locally advanced disease and locoregional relapses are not infrequent. These patients have a prolonged overall survival that may result in long periods of active disease and the possibility of requiring subsequent treatments. Recently, many new options have emerged as salvage therapies. This review offers a comprehensive discussion and considerations regarding surgery, active surveillance, radioactive iodine therapy, ultrasonography-guided percutaneous ablation, external beam radiotherapy, and systemic therapy for well-differentiated thyroid cancer based on relevant publications and current reference guidelines. We feel that the surgical member of the thyroid cancer management team is empowered by being aware and facile with all management options.
Labyrinthin Expression Is Associated with Poor Prognosis in Patients with Non-Small-Cell Lung Cancer
Authors: Ma Weijie , Zeng Jie , Montoya Dennis J. , Toomey Kyra , Zhou Chihong , Chen Shuai , Liu Dingning , Babich Michael , Radosevich James A. , Li Tianhong
Published: February 2023

To determine Labyrinthin (LAB) expression in non-small-cell lung cancer (NSCLC), we immunostained and scored for LAB immunohistochemistry (IHC) expression on sections of tissue microarrays (TMAs) prepared from 256 archival tissue blocks of NSCLC. Propensity-score-weighted Kaplan–Meier curves and weighted Cox models were used to associate LAB expression with overall survival. LAB mRNA expression was assessed in The Cancer Genome Atlas (TCGA) and correlated with clinical phenotype and outcome. Positive LAB IHC expression (>5% of tumor cells) was detected in 208/256 (81.3%) of NSCLC samples, and found in both lung adenocarcinomas (LUAD) and lung squamous cell cancer (LUSC). LAB positivity was associated with poor overall survival (HR = 3.56, 95% CI: 2.3–5.4; p < 0.0001) and high tumor differentiation grade or metastasis compared with negative LAB expression. Univariant and multivariate survival analyses demonstrated LAB expression as an independent prognostic factor for NSCLC patients. LAB RNA expression in TCGA-LUAD was higher in primary and advanced-stage tumors than in normal tissue, and was associated with poorer overall survival. No significant differences or associations were found with LAB RNA expression in TCGA-LUSC. The LAB IHC assay is being used to identify candidate cancer patients for the first-in-human phase I trial evaluating the LAB vaccines (UCDCC#296, NCT051013560).
Copolymerization of Norbornene and Methyl Acrylate by Nickel Catalyst Bearing 2-(Diarylphosphino)-N-phenylbenzenamine Ligands
Authors: Cao Lixin , Li Mingyuan , Cai Zhengguo
Published: February 2023

The synthesis of polar functionalized cyclic olefin copolymers (COCs) from the coordination copolymerization of norbornene (NB) and polar monomers catalyzed by late transition metal catalysts has been a recent research hotspot. However, few catalysts have achieved efficient copolymerization with commercial vinyl-type polar monomers, such as methyl acrylate (MA). In this contribution, nickel complexes bearing 2-(diarylphosphino)-N-phenylbenzenamine ligands were synthesized and applied as pre-catalysts to catalyze the (co)polymerization of norbornene. Upon the activation of methylaluminoxane (MAO), these nickel catalysts were active for norbornene polymerization with the highest activity achieved being 3.6 × 106 g mol−1 h−1 and the highest number average molecular weight (Mn) of polynorbornene (PNB) reaching 27.4 × 105 g mol−1. Moreover, these nickel catalysts also promoted the copolymerization of norbornene and MA to furnish high-molecular-weight NB/MA copolymers (Mn up to 6.20 × 104 g mol−1) with reasonable MA contents (3.07−5.90 mol%). The molecular weight of PNB and NB/MA copolymers obtained by the present nickel catalysts are remarkably higher than those of the (co)polymers from our previous reported dimethyl substituted phosphinobenzenamine nickel catalyst, suggesting significant progress in this field.
Preparation and Properties of g-C3N4-TiO2 Cement-Based Materials Supported by Recycled Concrete Powder
Authors: Yuan Teng , Yao Wu
Published: February 2023

In this paper, recycled concrete powder (RCP) is used as the carrier of g-C3N4-TiO2 instead of natural minerals. The prepared g-C3N4-TiO2/RCP composites were characterized by X-ray diffractometer, scanning electron microscope, infrared spectrometer, specific surface area analyzer, UV-visible spectrophotometer, and RhB solution degradation experiments. The results show that the rough, porous structure of RCP was beneficial to the stable load of g-C3N4-TiO2. Under the condition that the content of g-C3N4-TiO2 catalyst is constant, the agglomeration of g-C3N4-TiO2 can be reduced by using RCP as a carrier, thus improving its photocatalytic efficiency. Subsequently, g-C3N4-TiO2/RCP was loaded onto the surface of cement-based materials by coating bonding method to study its photocatalytic performance. It is found that the photocatalytic cement-based material has a similar degradation effect on the degradation of surface RhB as g-C3N4-TiO2/RCP in RhB solution. Our work may open up a new field for the recycling of RCP and provide new ideas for the development of photocatalytic cement-based materials.
Metallic–Organic Cages (MOCs) with Heterometallic Character: Flexibility-Enhancing MOFs
Authors: Posada-Pérez Sergio , Poater Jordi , Bahri-Laleh Naeimeh , Poater Albert
Published: February 2023

The dichotomy between metal–organic frameworks (MOFs) and metal–organic cages (MOCs) opens up the research spectrum of two fields which, despite having similarities, both have their advantages and disadvantages. Due to the fact that they have cavities inside, they also have applicability in the porosity sector. Bloch and coworkers within this evolution from MOFs to MOCs manage to describe a MOC with a structure of Cu2 paddlewheel Cu4L4 (L = bis(pyrazolyl)methane) with high precision thanks to crystallographic analyses of X-ray diffraction and also SEM-EDX. Then, also at the same level of concreteness, they were able to find the self-assembly of Pd(II)Cl2 moieties on the available nitrogen donor atoms leading to a [Cu4(L(PdCl2))4] structure. Here, calculations of the DFT density functional allow us to reach an unusual precision given the magnitude and structural complexity, explaining how a pyrazole ring of each bis(pyprazolyl)methane ligand must rotate from an anti to a syn conformation, and a truncation of the MOC structure allows us to elucidate, in the absence of the MOC constraint and its packing in the crystal, that the rotation is almost barrierless, as well as also explain the relative stability of the different conformations, with the anti being the most stable conformation. Characterization calculations with Mayer bond orders (MBO) and noncovalent interaction (NCI) plots discern what is important in the interaction of this type of cage with PdCl2 moieties, also CuCl2 by analogy, as well as simple molecules of water, since the complex is stable in this solvent. However, the L ligand is proved to not have the ability to stabilize an H2O molecule.
De Novo Synthesis of Polysubstituted 3-Hydroxypyridines Via “Anti-Wacker”-Type Cyclization
Authors: Ito Kazuya , Doi Takayuki , Tsukamoto Hirokazu
Published: February 2023

We report an efficient method to prepare polysubstituted 3-hydroxypyridines from amino acids, propargyl alcohols, and arylboronic acids. The process involves Pd(0)-catalyzed anti-selective arylative cyclizations of N-propargyl-N-tosyl-aminoaldehydes with arylboronic acids (“anti-Wacker”-type cyclization), oxidation of the resulting 5-substituted-3-hydroxy-1,2,3,6-tetrahydropyridines to 3-oxo derivatives, and elimination of p-toluenesulfinic acid. This method provides diverse polysubstituted 3-hydroxypyridines, whose hydroxy group can be further substituted by a cross-coupling reaction via a triflate.