bluuebunny/crossref_metadata_2025 huggingface dataset:
Review of the Spider Genus Linothele (Mygalomorphae, Dipluridae) from Ecuador—An Exceptional Case of Speciation in the Andes
Authors: Dupérré Nadine , Tapia Elicio , Bond Jason E.
Published: July 2023

The genus Linothele (Araneae: Dipluridae) from Ecuador is reviewed. A total of 38 new species are described; from the Andes: L. alausi n. sp. (♀), L. anabellecitae n. sp. (♀♂), L. angamarca n. sp. (♀♂), L. banos n. sp. (♀♂), L. canirasi n. sp. (♀), L. carchi n. sp. (♀), L. cayambe n. sp. (♀♂), L. cuencana n. sp. (♀♂), L. guacamayos n. sp. (♀), L. gualaquiza n. sp. (♀), L. guallupe n. sp. (♀), L. ilinizas n. sp. (♀♂), L. ireneae n. sp. (♀), L. jarrini n. sp. (♀), L. javieri n. sp. (♀), L. kaysi n. sp. (♀), L. lacocha n. sp. (♀), L. lloa n. sp. (♀♂), L. milleri n. sp. (♀♂), L. molleturo n. sp. (♀), L. otokiki n. sp. (♀), L. peguche n. sp. (♀♂), L. podocarpus n. sp. (♀), L. pomona n. sp. (♀), L. pristirana n. sp. (♀♂), L. pseudoquori n. sp. (♀♂), L. rionegro n. sp. (♀♂), L. sigchila n. sp. (♀♂), L. uvalino n. sp. (♀), L. victoria n. sp. (♀), L. yunguilla n. sp. (♀♂); from the Pacific region: L. costenita n. sp. (♀♂), L. troncal n. sp. (♀); and, from the Amazonian region: L. amazonica n. sp. (♀), L. archidona n. sp. (♀), L. condor n. sp. (♀♂), L. jatunsacha n. sp. (♀), L. otoyacu n. sp. (♀♂). All previously known Ecuadorian species are re-illustrated, and the males of L. cavicola, L. pukachumpi, and L. tsachilas are described for the first time. The geographical distribution of the genus Linothele through mainland Ecuador is discussed, and short-range endemic species are proposed. Distribution maps are provided for all species found in Ecuador. Finally, the synonymy of L. megatheloides under L. sericata is rejected.
Long-Term Trends in Inferred Continental Background Ozone in Eastern Australia
Authors: Riley Matthew L. , Jiang Ningbo , Duc Hiep Nguyen , Azzi Merched
Published: July 2023

A better understanding of background tropospheric ozone delivers multiple benefits. Robust estimates of regional background ozone are required to understand the limits of anthropogenic emissions controlling ozone reduction. Long-term estimates of background ozone assist in characterising changes in atmospheric composition and can help quantify the influence of human activity on the atmosphere. Background tropospheric ozone measurements representative of continental air masses are scarce in Australia. Here, we use k-means clustering to identify a cluster of measurements from the long-term air quality monitoring station at Oakdale, NSW, which are likely to be representative of background air. The cluster is associated with NOx-limited air masses of continental origin. From this analysis, we estimate background ozone representative of Eastern Australia. We find recent (2017–2022) mean ozone mixing ratios of 28.5 ppb and identify a statistically significant (α = 0.05) trend in the mean of +1.8 (1.0–2.8) ppb/decade. Our methods demonstrate that some long-term monitoring stations within or near urban areas can provide suitable conditions and datasets for regional Global Atmosphere Watch monitoring.
Medical 3D Printing Using Desktop Inverted Vat Photopolymerization: Background, Clinical Applications, and Challenges
Authors: Patel Parimal , Dhal Kashish , Gupta Rajul , Tappa Karthik , Rybicki Frank J. , Ravi Prashanth
Published: July 2023

Medical 3D printing is a complex, highly interdisciplinary, and revolutionary technology that is positively transforming the care of patients. The technology is being increasingly adopted at the Point of Care (PoC) as a consequence of the strong value offered to medical practitioners. One of the key technologies within the medical 3D printing portfolio enabling this transition is desktop inverted Vat Photopolymerization (VP) owing to its accessibility, high quality, and versatility of materials. Several reports in the peer-reviewed literature have detailed the medical impact of 3D printing technologies as a whole. This review focuses on the multitude of clinical applications of desktop inverted VP 3D printing which have grown substantially in the last decade. The principles, advantages, and challenges of this technology are reviewed from a medical standpoint. This review serves as a primer for the continually growing exciting applications of desktop-inverted VP 3D printing in healthcare.
Radiomics-Based Quality Control System for Automatic Cardiac Segmentation: A Feasibility Study
Authors: Liu Qiming , Lu Qifan , Chai Yezi , Tao Zhengyu , Wu Qizhen , Jiang Meng , Pu Jun
Published: July 2023

Purpose: In the past decade, there has been a rapid increase in the development of automatic cardiac segmentation methods. However, the automatic quality control (QC) of these segmentation methods has received less attention. This study aims to address this gap by developing an automatic pipeline that incorporates DL-based cardiac segmentation and radiomics-based quality control. Methods: In the DL-based localization and segmentation part, the entire heart was first located and cropped. Then, the cropped images were further utilized for the segmentation of the right ventricle cavity (RVC), myocardium (MYO), and left ventricle cavity (LVC). As for the radiomics-based QC part, a training radiomics dataset was created with segmentation tasks of various quality. This dataset was used for feature extraction, selection, and QC model development. The model performance was then evaluated using both internal and external testing datasets. Results: In the internal testing dataset, the segmentation model demonstrated a great performance with a dice similarity coefficient (DSC) of 0.954 for whole heart segmentations. Images were then appropriately cropped to 160 × 160 pixels. The models also performed well for cardiac substructure segmentations. The DSC values were 0.863, 0.872, and 0.940 for RVC, MYO, and LVC for 2D masks and 0.928, 0.886, and 0.962 for RVC, MYO, and LVC for 3D masks with an attention-UNet. After feature selection with the radiomics dataset, we developed a series of models to predict the automatic segmentation quality and its DSC value for the RVC, MYO, and LVC structures. The mean absolute values for our best prediction models were 0.060, 0.032, and 0.021 for 2D segmentations and 0.027, 0.017, and 0.011 for 3D segmentations, respectively. Additionally, the radiomics-based classification models demonstrated a high negative detection rate of >0.85 in all 2D groups. In the external dataset, models showed similar results. Conclusions: We developed a pipeline including cardiac substructure segmentation and QC at both the slice (2D) and subject (3D) levels. Our results demonstrate that the radiomics method possesses great potential for the automatic QC of cardiac segmentation.
“Could Patient Age and Gender, along with Mass Size, Be Predictive Factors for Benign Kidney Tumors?”: A Retrospective Analysis of 307 Consecutive Single Renal Masses Treated with Partial or Radical Nephrectomy
Authors: Baio Raffaele , Molisso Giovanni , Caruana Christian , Di Mauro Umberto , Intilla Olivier , Pane Umberto , D’Angelo Costantino , Campitelli Antonio , Pentimalli Francesca , Sanseverino Roberto
Published: July 2023

Due to the increased use of common and non-invasive abdominal imaging techniques over the last few decades, the diagnosis of about 60% of renal tumors is incidental. Contrast-enhancing renal nodules on computed tomography are diagnosed as malignant tumors, which are often removed surgically without first performing a biopsy. Most kidney nodules are renal cell carcinoma (RCC) after surgical treatment, but a non-negligible rate of these nodules may be benign on final pathology; as a result, patients undergo unnecessary surgery with an associated significant morbidity. Our study aimed to identify a subgroup of patients with higher odds of harboring benign tumors, who would hence benefit from further diagnostic examinations (such as renal biopsy) or active surveillance. We performed a retrospective review of the medical data, including pathology results, of patients undergoing surgery for solid renal masses that were suspected to be RCCs (for a total sample of 307 patients). Owing to the widespread use of common and non-invasive imaging techniques, the incidental diagnosis of kidney tumors has become increasingly common. Considering that a non-negligible rate of these tumors is found to be benign after surgery at pathological examination, it is crucial to identify features that can correctly diagnose a mass as benign or not. According to our study results, female sex and tumor size ≤ 3 cm were independent predictors of benign disease. Contrary to that demonstrated by other authors, increasing patient age was also positively linked to a greater risk of malign pathology.
Hydrogel-Based Bioelectronics and Their Applications in Health Monitoring
Authors: Hua Jiangbo , Su Mengrui , Sun Xidi , Li Jiean , Sun Yuqiong , Qiu Hao , Shi Yi , Pan Lijia
Published: July 2023

Flexible bioelectronics exhibit promising potential for health monitoring, owing to their soft and stretchable nature. However, the simultaneous improvement of mechanical properties, biocompatibility, and signal-to-noise ratio of these devices for health monitoring poses a significant challenge. Hydrogels, with their loose three-dimensional network structure that encapsulates massive amounts of water, are a potential solution. Through the incorporation of polymers or conductive fillers into the hydrogel and special preparation methods, hydrogels can achieve a unification of excellent properties such as mechanical properties, self-healing, adhesion, and biocompatibility, making them a hot material for health monitoring bioelectronics. Currently, hydrogel-based bioelectronics can be used to fabricate flexible bioelectronics for motion, bioelectric, and biomolecular acquisition for human health monitoring and further clinical applications. This review focuses on materials, devices, and applications for hydrogel-based bioelectronics. The main material properties and research advances of hydrogels for health monitoring bioelectronics are summarized firstly. Then, we provide a focused discussion on hydrogel-based bioelectronics for health monitoring, which are classified as skin-attachable, implantable, or semi-implantable depending on the depth of penetration and the location of the device. Finally, future challenges and opportunities of hydrogel-based bioelectronics for health monitoring are envisioned.
Co-Producing Phycocyanin and Bioplastic in Arthrospira platensis Using Carbon-Rich Wastewater
Authors: Shayesteh Hajar , Laird Damian W. , Hughes Leonie J. , Nematollahi Mohammad A. , Kakhki Amin Mirshamsi , Moheimani Navid R.
Published: July 2023

Microalgae can treat waste streams containing elevated levels of organic carbon and nitrogen. This process can be economically attractive if high value products are created simultaneously from the relatively low-cost waste stream. Co-production of two high value microalgal products, phycocyanin and polyhydroxybutyrate (PHB), was investigated using non-axenic Arthrospira platensis MUR126 and supplemental organic carbon (acetate, oxalate, glycerol and combinations). All supplemented cultures had higher biomass yield (g/L) than photoautotrophic control. All cultures produced PHB (3.6–7.8% w/w), except the control and those fed oxalate. Supplemented cultures showed a two to three-fold increase in phycocyanin content over the eight-day cultivation. Results indicate co-production of phycocyanin and PHB is possible in A. platensis, using mixed-waste organic carbon. However, supplementation resulted in growth of extremophile bacteria, particularly in cultures fed glycerol, and this had a negative impact on culture health. Refinement of the carbon dosing rate is required to minimise impacts of native bacterial contamination.
How to Support Expanding Sales Channels of Agri-Food Products in New Markets: Healthiness and New Experiences of Tunisian Olive Oil
Authors: Oe Hiroko , Yamaoka Yasuyuki
Published: July 2023

This study addresses the empirical problem of improving sales channels in countries like Tunisia, with a specific focus on the sales channels of Tunisian olive oil. The authors aim to explore this problem within the theoretical framework of sales channels and emphasize the contribution of their research to enhancing sales channels and accessing new markets for Tunisian olive oil. To achieve these goals, the authors conducted a study with a specific research objective: to examine the factors influencing consumer behavior and perceptions towards olive oil. By doing so, this research contributes to a better understanding of the challenges and opportunities of expanding sales channels and supports the development of sustainable agribusiness. Additionally, the authors highlight the importance of advertising healthy food with good quality based on an ethical production process that emphasizes accountability and transparency. They argue that these ethical practices can serve as competitive strengths for agri-food producers in emerging markets as they explore new market opportunities. Overall, this research not only addresses the need for improving sales channels in Tunisia but also provides insights into consumer behavior, highlights the significance of ethical production processes, and supports the competitiveness of agri-food producers in emerging markets.
Appendiceal Mucinous Neoplasms: From Clinic to Pathology and Prognosis
Authors: González Bayón Luis , Martín Román Lorena , Lominchar Pablo Lozano
Published: July 2023

Appendiceal mucinous neoplasms have been classified differently over time causing confusion when comparing results between working groups in this field and establishing a prognosis of the disease. A historical perspective of the different classification systems of these tumors is essential for the understanding of the evolution of concepts and histopathological definitions that have led up to the present moment. We carried out a systematic review of the pathological classifications of appendiceal mucinous tumors and how they have included the new criteria resulting from clinical and pathological research. The latest classifications by PSOGI and AJCC 8th edition Cancer Staging have made a great effort to incorporate the new pathological descriptions and develop prognostic groups. The introduction of these new classification systems has posed the challenge of verifying how they adapt to our casuistry and which one defines best the prognosis of our patients. We reclassified our series of patients treated for mucinous appendiceal tumors with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy following the PSOGI and the AJCC 8th edition criteria and concluded that both classifications correspond well with the OS and DFS of these patients, with some advantage relative to the PSOGI classification due to a better histopathological description of the different groups.
Photodynamic Therapy for Glioblastoma: Illuminating the Path toward Clinical Applicability
Authors: Bhanja Debarati , Wilding Hannah , Baroz Angel , Trifoi Mara , Shenoy Ganesh , Slagle-Webb Becky , Hayes Daniel , Soudagar Yasaman , Connor James , Mansouri Alireza
Published: July 2023

Glioblastoma (GBM) is the most common adult brain cancer. Despite extensive treatment protocols comprised of maximal surgical resection and adjuvant chemo–radiation, all glioblastomas recur and are eventually fatal. Emerging as a novel investigation for GBM treatment, photodynamic therapy (PDT) is a light-based modality that offers spatially and temporally specific delivery of anti-cancer therapy with limited systemic toxicity, making it an attractive option to target GBM cells remaining beyond the margins of surgical resection. Prior PDT approaches in GBM have been predominantly based on 5-aminolevulinic acid (5-ALA), a systemically administered drug that is metabolized only in cancer cells, prompting the release of reactive oxygen species (ROS), inducing tumor cell death via apoptosis. Hence, this review sets out to provide an overview of current PDT strategies, specifically addressing both the potential and shortcomings of 5-ALA as the most implemented photosensitizer. Subsequently, the challenges that impede the clinical translation of PDT are thoroughly analyzed, considering relevant gaps in the current PDT literature, such as variable uptake of 5-ALA by tumor cells, insufficient tissue penetrance of visible light, and poor oxygen recovery in 5-ALA-based PDT. Finally, novel investigations with the potential to improve the clinical applicability of PDT are highlighted, including longitudinal PDT delivery, photoimmunotherapy, nanoparticle-linked photosensitizers, and near-infrared radiation. The review concludes with commentary on clinical trials currently furthering the field of PDT for GBM. Ultimately, through addressing barriers to clinical translation of PDT and proposing solutions, this review provides a path for optimizing PDT as a paradigm-shifting treatment for GBM.
NRK-ABMIL: Subtle Metastatic Deposits Detection for Predicting Lymph Node Metastasis in Breast Cancer Whole-Slide Images
Authors: Sajjad Usama , Rezapour Mostafa , Su Ziyu , Tozbikian Gary H. , Gurcan Metin N. , Niazi M. Khalid Khan
Published: July 2023

The early diagnosis of lymph node metastasis in breast cancer is essential for enhancing treatment outcomes and overall prognosis. Unfortunately, pathologists often fail to identify small or subtle metastatic deposits, leading them to rely on cytokeratin stains for improved detection, although this approach is not without its flaws. To address the need for early detection, multiple-instance learning (MIL) has emerged as the preferred deep learning method for automatic tumor detection on whole slide images (WSIs). However, existing methods often fail to identify some small lesions due to insufficient attention to small regions. Attention-based multiple-instance learning (ABMIL)-based methods can be particularly problematic because they may focus too much on normal regions, leaving insufficient attention for small-tumor lesions. In this paper, we propose a new ABMIL-based model called normal representative keyset ABMIL (NRK-ABMIL), which addresseses this issue by adjusting the attention mechanism to give more attention to lesions. To accomplish this, the NRK-ABMIL creates an optimal keyset of normal patch embeddings called the normal representative keyset (NRK). The NRK roughly represents the underlying distribution of all normal patch embeddings and is used to modify the attention mechanism of the ABMIL. We evaluated NRK-ABMIL on the publicly available Camelyon16 and Camelyon17 datasets and found that it outperformed existing state-of-the-art methods in accurately identifying small tumor lesions that may spread over a few patches. Additionally, the NRK-ABMIL also performed exceptionally well in identifying medium/large tumor lesions.
Tebentafusp in Patients with Metastatic Uveal Melanoma: A Real-Life Retrospective Multicenter Study
Authors: Tomsitz Dirk , Ruf Theresa , Heppt Markus , Staeger Ramon , Ramelyte Egle , Dummer Reinhard , Garzarolli Marlene , Meier Friedegund , Meier Eileen , Richly Heike , Gromke Tanja , Siveke Jens T. , Franklin Cindy , Klespe Kai-Christian , Mauch Cornelia , Kilian Teresa , Seegräber Marlene , Schilling Bastian , French Lars E. , Berking Carola , Heinzerling Lucie
Published: July 2023

Background: Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM) after proving to have survival benefits in a first-line setting. Patients and Methods: This retrospective, multicenter study analyzed the outcomes and safety of tebentafusp therapy in 78 patients with mUM. Results: Patients treated with tebentafusp had a median PFS of 3 months (95% CI 2.7 to 3.3) and a median OS of 22 months (95% CI 10.6 to 33.4). In contrast to a published Phase 3 study, our cohort had a higher rate of patients with elevated LDH (65.4% vs. 35.7%) and included patients with prior systemic and local ablative therapies. In patients treated with tebentafusp following ICI, there was a trend for a longer median OS (28 months, 95% CI 26.9 to 29.1) compared to the inverse treatment sequence (24 months, 95% CI 13.0 to 35.0, p = 0.257). The most common treatment-related adverse events were cytokine release syndrome in 71.2% and skin toxicity in 53.8% of patients. Tumor lysis syndrome occurred in one patient. Conclusions: Data from this real-life cohort showed a median PFS/OS similar to published Phase 3 trial data. Treatment with ICI followed by tebentafusp may result in longer PFS/OS compared to the inverse treatment sequence.
Real World Experience of Second-Line Treatment Strategies after Palbociclib and Letrozole: Overall Survival in Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer
Authors: Kim Ji-Yeon , Shin Junghoon , Ahn Jin Seok , Park Yeon Hee , Im Young-Hyuck
Published: July 2023

Background: We analyzed real-world practice of second-line treatment in hormone receptor (HR)+ human epidermal growth factor receptor-2 (HER2)− metastatic breast cancer (MBC) following the first-line CDK4/6 inhibitor with letrozole. In addition, we evaluated the relationship between second-line treatment strategies and survival outcome. Methods: Using the clinical data warehouse, clinical information including MBC diagnosis, treatment and survival outcomes were collected. Results: In total, 305 patients were treated with the first-line palbociclib plus letrozole, and we evaluated 166 patients who were treated with second-line treatment. Of the 166 patients, 28.5% were treated with capecitabine (C), followed by exemestane with everolimus (EE) (27.3%) or cytotoxic chemotherapy other than capecitabine (T) (18.8%) and fulvestrant-based treatment or endocrine monotherapy (F) (12.7%). Eighteen patients (10.9%) were enrolled in clinical trials (CT). With regard to treatment strategies, and the median progression-free survival of second-line treatment in a metastatic setting (PFS2) was 7.4 months with C, 5.2 months with EE, 4.8 months with T, 3.6 months with F, and 3.6 months with CT (p = 0.066). In patients with visceral organ disease progression, C (31.3%) or T(31.3%) was the most common second-line treatment followed by EE (21.9%). Most of the 47 patients with bone metastasis alone were treated with EE (38.2%), followed by C (23.4%) and F (21.3%) (p = 0.008). The median overall survival of second-line treatment in a metastatic setting (OS2) was 42.3 months with C, 35.7 months with F, 30.7 months with EE, and 23.1 months with T. The median OS2 for those in CT was not reached (p = 0.064). ER driven BC, disease progression site and PFS2 were associated with OS and OS2 in HR+HER2− MBC (ps < 0.05). Conclusions: We suggested the second line treatment strategy was important to improve prognosis in patients with HR+/HER2− MBC, especially given the recent standardization of first-line treatment and the many available second-line options.
Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1
Authors: Khazan Negar , Quarato Emily R. , Singh Niloy A. , Snyder Cameron W. A. , Moore Taylor , Miller John P. , Yasui Masato , Teramoto Yuki , Goto Takuro , Reshi Sabeeha , Hong Jennifer , Zhang Naixin , Pandey Diya , Srivastava Priyanka , Morell Alexandra , Kawano Hiroki , Kawano Yuko , Conley Thomas , Sahasrabudhe Deepak M. , Yano Naohiro , Miyamoto Hiroshi , Aljitawi Omar , Liesveld Jane , Becker Michael W. , Calvi Laura M. , Zhovmer Alexander S. , Tabdanov Erdem D. , Dokholyan Nikolay V. , Linehan David C. , Hansen Jeanne N. , Gerber Scott A. , Sharon Ashoke , Khera Manoj K. , Jurutka Peter W. , Rochel Natacha , Kim Kyu Kwang , Rowswell-Turner Rachael B. , Singh Rakesh K. , Moore Richard G.
Published: July 2023

Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.
An Apparent Diffusion Coefficient-Based Machine Learning Model Can Improve Prostate Cancer Detection in the Grey Area of the Prostate Imaging Reporting and Data System Category 3: A Single-Centre Experience
Authors: Gaudiano Caterina , Mottola Margherita , Bianchi Lorenzo , Corcioni Beniamino , Braccischi Lorenzo , Taninokuchi Tomassoni Makoto , Cattabriga Arrigo , Cocozza Maria , Giunchi Francesca , Schiavina Riccardo , Fanti Stefano , Fiorentino Michelangelo , Brunocilla Eugenio , Mosconi Cristina , Bevilacqua Alessandro
Published: July 2023

The Prostate Imaging and Reporting Data System (PI-RADS) has a key role in the management of prostate cancer (PCa). However, the clinical interpretation of PI-RADS 3 score lesions may be challenging and misleading, thus postponing PCa diagnosis to biopsy outcome. Multiparametric magnetic resonance imaging (mpMRI) radiomic analysis may represent a stand-alone noninvasive tool for PCa diagnosis. Hence, this study aims at developing a mpMRI-based radiomic PCa diagnostic model in a cohort of PI-RADS 3 lesions. We enrolled 133 patients with 155 PI-RADS 3 lesions, 84 of which had PCa confirmation by fusion biopsy. Local radiomic features were generated from apparent diffusion coefficient maps, and the four most informative were selected using LASSO, the Wilcoxon rank-sum test (p < 0.001), and support vector machines (SVMs). The selected features where augmented and used to train an SVM classifier, externally validated on a holdout subset. Linear and second-order polynomial kernels were exploited, and their predictive performance compared through receiver operating characteristics (ROC)-related metrics. On the test set, the highest performance, equally for both kernels, was specificity = 76%, sensitivity = 78%, positive predictive value = 80%, and negative predictive value = 74%. Our findings substantially improve radiologist interpretation of PI-RADS 3 lesions and let us advance towards an image-driven PCa diagnosis.
Prediction of 2-[18F]FDG PET-CT SUVmax for Adrenal Mass Characterization: A CT Radiomics Feasibility Study
Authors: Stanzione Arnaldo , Cuocolo Renato , Bombace Claudia , Pesce Ilaria , Mainolfi Ciro Gabriele , De Giorgi Marco , Delli Paoli Gregorio , La Selva Pasquale , Petrone Jessica , Camera Luigi , Klain Michele , Del Vecchio Silvana , Cuocolo Alberto , Maurea Simone
Published: July 2023

Background: Indeterminate adrenal masses (AM) pose a diagnostic challenge, and 2-[18F]FDG PET-CT serves as a problem-solving tool. Aim of this study was to investigate whether CT radiomics features could be used to predict the 2-[18F]FDG SUVmax of AM. Methods: Patients with AM on 2-[18F]FDG PET-CT scan were grouped based on iodine contrast injection as CT contrast-enhanced (CE) or CT unenhanced (NCE). Two-dimensional segmentations of AM were manually obtained by multiple operators on CT images. Image resampling and discretization (bin number = 16) were performed. 919 features were calculated using PyRadiomics. After scaling, unstable, redundant, and low variance features were discarded. Using linear regression and the Uniform Manifold Approximation and Projection technique, a CT radiomics synthetic value (RadSV) was obtained. The correlation between CT RadSV and 2-[18F]FDG SUVmax was assessed with Pearson test. Results: A total of 725 patients underwent PET-CT from April 2020 to April 2021. In 150 (21%) patients, a total of 179 AM (29 bilateral) were detected. Group CE consisted of 84 patients with 108 AM (size = 18.1 ± 4.9 mm) and Group NCE of 66 patients with 71 AM (size = 18.5 ± 3.8 mm). In both groups, 39 features were selected. No statisticallyf significant correlation between CT RadSV and 2-[18F]FDG SUVmax was found (Group CE, r = 0.18 and p = 0.058; Group NCE, r = 0.13 and p = 0.27). Conclusions: It might not be feasible to predict 2-[18F]FDG SUVmax of AM using CT RadSV. Its role as a problem-solving tool for indeterminate AM remains fundamental.
Transperineal US-MRI Fusion-Guided Biopsy for the Detection of Clinical Significant Prostate Cancer: A Systematic Review and Meta-Analysis Comparing Cognitive and Software-Assisted Technique
Authors: Pirola Giacomo Maria , Castellani Daniele , Orecchia Luca , Giulioni Carlo , Gubbiotti Marilena , Rubilotta Emanuele , Maggi Martina , Teoh Jeremy Yuen-Chun , Gauhar Vineet , Naselli Angelo
Published: July 2023

Introduction: We aimed to find potential differences in clinically significant prostate cancer (csPCa) detection rates between transperineal software-assisted fusion biopsy (saFB) and cognitive fusion biopsies (cFB). Methods: A systematic review of the literature was performed to identify comparative studies using PubMed, EMBASE, and Scopus according to the PICOS criteria. Cancer detection and complication rates were pooled using the Cochran–Mantel–Haenszel method with the random effect model and reported as odds ratios (ORs), 95% confidence intervals (CI), and p-values. A meta-analysis was performed using Review Manager (RevMan) 5.4 software by Cochrane Collaboration. The quality assessment of the included studies was performed using the Cochrane Risk of Bias tool, using RoB 2 for randomized studies and ROBINS-I for retrospective and nonrandomized ones. Results: Eight studies were included for the meta-analysis, including 1149 cases in software-based and 963 cases in cognitive fusion biopsy. The detection rates of csPCa were similar between the two groups (OR 1.01, 95% CI 0.74–1.37, p = 0.95). Study heterogeneity was low (I2 55%). Conclusion: There is no actual evidence of the superiority of saFB over cFB in terms of the csPCa detection rate. Operator experience and software availability can drive the choice of one fusion technique over the other.
Co-Targeting FASN and mTOR Suppresses Uveal Melanoma Growth
Authors: Han Anna , Mukha Dzmitry , Chua Vivian , Purwin Timothy J. , Tiago Manoela , Modasia Bhavik , Baqai Usman , Aumiller Jenna L. , Bechtel Nelisa , Hunter Emily , Danielson Meggie , Terai Mizue , Wedegaertner Philip B. , Sato Takami , Landreville Solange , Davies Michael A. , Kurtenbach Stefan , Harbour J. William , Schug Zachary T. , Aplin Andrew E.
Published: July 2023

Uveal melanoma (UM) displays a high frequency of metastasis; however, effective therapies for metastatic UM are limited. Identifying unique metabolic features of UM may provide a potential targeting strategy. A lipid metabolism protein expression signature was induced in a normal choroidal melanocyte (NCM) line transduced with GNAQ (Q209L), a driver in UM growth and development. Consistently, UM cells expressed elevated levels of fatty acid synthase (FASN) compared to NCMs. FASN upregulation was associated with increased mammalian target of rapamycin (mTOR) activation and sterol regulatory element-binding protein 1 (SREBP1) levels. FASN and mTOR inhibitors alone significantly reduced UM cell growth. Concurrent inhibition of FASN and mTOR further reduced UM cell growth by promoting cell cycle arrest and inhibiting glucose utilization, TCA cycle metabolism, and de novo fatty acid biosynthesis. Our findings indicate that FASN is important for UM cell growth and co-inhibition of FASN and mTOR signaling may be considered for treatment of UM.
Multicenter Observational Retrospective Study on Febrile Events in Patients with Acute Myeloid Leukemia Treated with Cpx-351 in “Real-Life”: The SEIFEM Experience
Authors: Fianchi Luana , Guolo Fabio , Marchesi Francesco , Cattaneo Chiara , Gottardi Michele , Restuccia Francesco , Candoni Anna , Ortu La Barbera Elettra , Fazzi Rita , Pasciolla Crescenza , Finizio Olimpia , Fracchiolla Nicola , Delia Mario , Lessi Federica , Dargenio Michelina , Bonuomo Valentina , Del Principe Maria Ilaria , Zappasodi Patrizia , Picardi Marco , Basilico Claudia , Piedimonte Monica , Minetto Paola , Giordano Antonio , Chiusolo Patrizia , Prezioso Lucia , Buquicchio Caterina , Melillo Lorella Maria Antonia , Zama Daniele , Farina Francesca , Mancini Valentina , Terrenato Irene , Rondoni Michela , Urbino Irene , Tumbarello Mario , Busca Alessandro , Pagano Livio
Published: July 2023

In the present study, we aimed to evaluate the absolute risk of infection in the real-life setting of AML patients treated with CPX-351. The study included all patients with AML from 30 Italian hematology centers of the SEIFEM group who received CPX-351 from July 2018 to June 2021. There were 200 patients included. Overall, 336 CPX-351 courses were counted: all 200 patients received the first induction cycle, 18 patients (5%) received a second CPX-351 induction, while 86 patients (26%) proceeded with the first CPX-351 consolidation cycle, and 32 patients (10%) received a second CPX-351 consolidation. A total of 249 febrile events were recorded: 193 during the first or second induction, and 56 after the first or second consolidation. After the diagnostic work-up, 92 events (37%) were classified as febrile neutropenia of unknown origin (FUO), 118 (47%) were classifiable as microbiologically documented infections, and 39 (17%) were classifiable as clinically documented infections. The overall 30-day mortality rate was 14% (28/200). The attributable mortality–infection rate was 6% (15/249). A lack of response to the CPX-351 treatment was the only factor significantly associated with mortality in the multivariate analysis [p-value: 0.004, OR 0.05, 95% CI 0.01–0.39]. Our study confirms the good safety profile of CPX-351 in a real-life setting, with an incidence of infectious complications comparable to that of the pivotal studies; despite prolonged neutropenia, the incidence of fungal infections was low, as was infection-related mortality.
Residues from Homologous Transmembrane Helices 4 and 10 Are Critical for P-Glycoprotein (ABCB1)-Mediated Drug Transport
Authors: Rahman Hadiar , Ware Mark J. , Sajid Andaleeb , Lusvarghi Sabrina , Durell Stewart R. , Ambudkar Suresh V.
Published: July 2023

P-glycoprotein (P-gp, ABCB1) transports structurally dissimilar hydrophobic and amphipathic compounds, including anticancer drugs, thus contributing to multidrug-resistant cancer. Cryo-EM structures of human P-gp revealed that TMHs 4 and 10 contribute to the formation of the drug-binding cavity and undergo conformational changes during drug transport. To assess the role of the conformational changes in TMH4 and TMH10 during drug transport, we generated two mutants (TMH4-7A and TMH10-7A), each containing seven alanine substitutions. Analysis of the drug efflux function of these mutants using 15 fluorescent substrates revealed that most of the substrates were transported, indicating that even seven mutations in an individual helix have no significant effect on transport function. We then designed the TMH4,10-14A mutant combining seven mutations in both TMHs 4 and 10. Interestingly, when the TMH4,10-14A mutant was tested with 15 substrates, there was no efflux observed for fourteen. The basal ATPase activity of the TMH4,10-14A mutant, similar to that of the WT protein, was inhibited by zosuquidar but was not stimulated by verapamil or rhodamine 6G. Molecular dynamics simulations indicated that the mutations cause TMHs 4 and 10 to pack tighter to their proximal helices, reducing their independent mobility. In aggregate, our findings demonstrate the critical role of the residues of homologous TMHs 4 and 10 for substrate transport, consistent with conformational changes observed in the structure of P-gp.
An Emerging Role for Sigma Receptor 1 in Personalized Treatment of Breast Cancer
Authors: Robinson Taylor S. , Osman Mahasin A.
Published: July 2023

Despite the major progress in treating breast cancer, recurrence remains a problem and types such as triple-negative breast cancer still lack targeted medicine. The orphan Sigma receptor1 (SigmaR1) has emerged as a target in breast cancer, but its mechanism of action is unclear and hinders clinical utility. SigmaR1 is widely expressed in organ tissues and localized to various sub-cellular compartments, particularly the endoplasmic reticulum (ER), the mitochondrial-associated membranes (MAMs) and the nuclear envelope. As such, it involves diverse cellular functions, including protein quality control/ER stress, calcium signaling, cholesterol homeostasis, mitochondrial integrity and energy metabolism. Consequently, SigmaR1 has been implicated in a number of cancers and degenerative diseases and thus has been intensively pursued as a therapeutic target. Because SigmaR1 binds a number of structurally unrelated ligands, it presents an excellent context-dependent therapeutic target. Here, we review its role in breast cancer and the current therapies that have been considered based on its known functions. As SigmaR1 is not classified as an oncoprotein, we propose a model in which it serves as an oligomerization adaptor in key cellular pathways, which may help illuminate its association with variable diseases and pave the way for clinical utility in personalized medicine.
Tas-102 for Refractory Metastatic Colorectal Cancer: A Multicenter Retrospective Cohort Study
Authors: Conti Matteo , Bolzacchini Elena , Luchena Giovanna , Bertu’ Lorenza , Tagliabue Paola , Aglione Stefania , Ardizzoia Antonio , Arnoffi Jessica , Guida Francesco Maria , Bertolini Alessandro , Pastorini Alessandro , Duro Maria , Bettega Donato , Roda’ Giovambattista , Artale Salvatore , Squizzato Alessandro , Giordano Monica
Published: July 2023

Trifluridine/tipiracil (TAS-102) is an oral chemotherapy approved for the treatment of metastatic colorectal cancer. The efficacy and tolerability of TAS-102 were shown in phase II-III clinical trials and in several real-life studies. The elderly and other special subgroups are underrepresented in published literature. We conducted a retrospective multicenter study to assess the effectiveness and safety of TAS-102 in consecutive patients with pretreated mCRC. In particular, we estimated the effectiveness and safety of TAS-102 in elderly patients (aged ≥70, ≥75 and ≥80 years) and in special subgroups, e.g., patients with concomitant heart disease. One hundred and sixty patients were enrolled. In particular, 71 patients (44%) were 70 years of age or older, 50 (31%) were 75 years of age or older, and 23 (14%) were 80 years of age or older. 19 patients (12%) had a concomitant chronic heart disease, three (2%) patients were HIV positive, and one (<1%) patient had a DPYD gene polymorphism. In 115 (72%) cases TAS-102 was administered as a third-line treatment. The median overall survival (OS) in the overall population was 8 months (95% confidence interval [CI], 6–9), while the median progression-free survival (PFS) was 3 months (95% CI, 3–4). No significant age-related reduction in effectiveness was observed in the subpopulations of elderly patients included. The toxicity profile was acceptable in both the whole and subgroups’ population. Our study confirms the effectiveness and safety of TAS-102 in patients with pretreated mCRC, suggesting a similar risk-benefit profile in the elderly.
The Real-World Evidence on the Fragility and Its Impact on the Choice of Treatment Regimen in Newly Diagnosed Patients with Multiple Myeloma over 75 Years of Age
Authors: Tyczyńska Agata , Krzempek Marcela Krzysława , Cortez Alexander Jorge , Jurczyszyn Artur , Godlewska Katarzyna , Ciepłuch Hanna , Subocz Edyta , Hałka Janusz , Kulikowska de Nałęcz Anna , Wiśniewska Anna , Świderska Alina , Waszczuk-Gajda Anna , Drozd-Sokołowska Joanna , Guzicka-Kazimierczak Renata , Wiśniewski Kamil , Porowska Agnieszka , Knopińska-Posłuszny Wanda , Kłoczko Janusz , Rzepecki Piotr , Woszczyk Dariusz , Symonowicz Hanna , Basak Grzegorz Władysław , Zdziarska Barbara , Jamroziak Krzysztof , Zaucha Jan M.
Published: July 2023

Fragility scales are intended to help in therapeutic decisions. Here, we asked if the fragility assessment in MM patients ≥ 75 years old qualified for treatment by the local physician correlates with the choice of treatment: a two- or three-drug regimens. Between 7/2018 and 12/2019, we prospectively enrolled 197 MM patients at the start of treatment from the 13 Polish Myeloma Group centers. The data to assess fragility were prospectively collected, but centrally assessed fragility was not disclosed to the local center. The activity of daily living (ADL) could be assessed in 192 (97.5%) and was independent in 158 (80.2%), moderately impaired in 23 (11.7%), and 11 (5.6%) in completely dependent. Patients with more than three comorbidities made up 26.9% (53 patients). Thus, according to the Palumbo calculator, 43 patients were in the intermediate fitness group (21.8%), and the rest belonged to the frailty group (153, 77.7%). Overall, 79.7% of patients (157) received three-drug regimens and 20.3% (40) received two-drug regimens. In each ECOG group, more than three out of four patients received three-drug regimens. According to the ADL scale, 82.3% of the independent 65.2% of moderately impaired, and 81.8% of the dependent received three-drug regimens. Out of 53 patients with at least four comorbidities, 71.7% received three-drug regimens, and the rest received two-drug regimens. Thirty-four patients from the intermediate fit group (79.0%), and 123 (79.9%) from the frail group received three-drug regimens. Early mortality occurred in 25 patients (12.7%). No one discontinued treatment due to toxicity. To conclude, MM patients over 75 are mainly treated with triple-drug regimens, not only in reduced doses, regardless of their frailty scores. However, the absence of prospective fragility assessment did not negatively affect early mortality and the number of treatment discontinuations, which brings into question the clinical utility of current fragility scales in everyday practice.
Surgery in Recurrent Ovarian Cancer: A Meta-Analysis
Authors: Climent Maria Teresa , Serra Anna , Llueca Maria , Llueca Antoni
Published: July 2023

Background: The second cytoreductive surgery performed for a patient who has recurrent ovarian cancer remains controversial. Our study analyzes overall survival (OS) and disease-free survival (DFS) for cytoreductive surgery in addition to chemotherapy in recurrent ovarian cancer instead of chemotherapy alone. Methods: A meta-analysis was conducted using PubMed and the Cochrane database of systematic reviews to select randomized controlled studies. In total, three randomized studies were used, employing a total of 1249 patients. Results: The results of our meta-analysis of these randomized controlled trials identified significant differences in OS (HR = 0.83, IC 95% 0.70–0.99, p < 0.04) and DFS (HR = 0.63, IC 95% 0.55–0.72, p < 0.000001). A subgroup analysis comparing complete cytoreductive surgery and surgery with residual tumor achieved better results for both OS (HR = 0.65, IC 95% 0.49–0.86, p = 0.002) and DFS (HR = 0.67, IC 95% 0.53–0.82, p = 0.0008), with statistical significance. Conclusions: A complete secondary cytoreductive surgery (SCS) in recurrent ovarian cancer (ROC) demonstrates an improvement in the OS and DFS, and this benefit is most evident in cases where complete cytoreductive surgery is achieved. The challenge is the correct patient selection for secondary cytoreductive surgery to improve the results of this approach.
Olive Leaf Extract (OLE) as a Novel Antioxidant That Ameliorates the Inflammatory Response in Cystic Fibrosis
Authors: Allegretta Caterina , Difonzo Graziana , Caponio Francesco , Tamma Grazia , Laselva Onofrio
Published: July 2023

The deletion of phenylalanine at position 508 (F508del) produces a misfolded CFTR protein that is retained in the ER and degraded. The lack of normal CFTR channel activity is associated with chronic infection and inflammation which are the primary causes of declining lung function in Cystic Fibrosis (CF) patients. Moreover, LPS-dependent oxidative stress downregulates CFTR function in airway epithelial cells. Olive leaf extract (OLE) is used in traditional medicine for its effects, including anti-oxidant and anti-inflammatory ones. We found that OLE decreased the intracellular ROS levels in a dose–response manner in CFBE cells. Moreover, OLE attenuates the inflammatory response to LPS or IL-1β/TNFα stimulation, mimicking the infection and inflammatory status of CF patients, in CFBE and primary nasal epithelial (HNE) cells. Furthermore, we demonstrated that OLE restored the LPS-mediated decrease of TrikfaftaTM-dependent F508del-CFTR function in CFBE and HNE cultures. These findings provide strong evidence of OLE to prevent redox imbalance and inflammation that can cause chronic lung damage by enhancing the antioxidant activity and attenuating inflammation in CF airway epithelial cells. Additionally, OLE might be used in combination with CFTR modulators therapy to improve their efficacy in CF patients.
Carbonate-Hydroxyapatite Cement: The Effect of Composition on Solubility In Vitro and Resorption In Vivo
Authors: Lukina Yulia , Bionyshev-Abramov Leonid , Kotov Sergey , Serejnikova Natalya , Smolentsev Dmitriiy , Sivkov Sergey
Published: July 2023

The rate of resorption of calcium phosphate self-hardening materials for bone regeneration can be changed by changing the phase composition. The Ca3(PO4)2/CaCO3/Ca(H2PO4)2·H2O/Na2HPO4·12H2O system is important for the synthesis of self-curing bioactive materials with variable resorption rates by changing the ratios of the initial components. Cement compositions in twelve figurative points of a four-component composition diagram at a fixed content in the α-Ca3(PO4)2 system were studied with XRD, FTIR, SEM, calorimetric, and volumetric methods to obtain an idea of the effect of composition on solubility in vitro and resorption in vivo. It was found that the presence of the highly resorbable phase of dicalcium phosphate dihydrate in cement and the substitution of phosphate ions with the carbonate ions of hydroxyapatite increased solubility in vitro and resorption in vivo. The obtained results confirm the possibility of changing the solubility of a final product in the Ca3(PO4)2/CaCO3/Ca(H2PO4)2·H2O/Na2HPO4·12H2O system by changing the ratio of the initial components.