bluuebunny/crossref_metadata_2025 huggingface dataset:
PD-1/PD-L1 Inhibitors Response in Triple-Negative Breast Cancer: Can Long Noncoding RNAs Be Associated?
Authors: Mathias Carolina , Kozak Vanessa Nascimento , Magno Jessica Maria , Baal Suelen Cristina Soares , dos Santos Victor Henrique Apolonio , Ribeiro Enilze Maria de Souza Fonseca , Gradia Daniela Fiori , Castro Mauro Antonio Alves , Carvalho de Oliveira Jaqueline
Published: September 2023

As immune checkpoint inhibitors (ICI) emerge as a paradigm-shifting treatment option for patients with advanced or metastatic cancer, there is a growing demand for biomarkers that can distinguish which patients are likely to benefit. In the case of triple-negative breast cancer (TNBC), characterized by a lack of therapeutic targets, pembrolizumab approval for high-risk early-stage disease occurred regardless of PD-L1 status, which keeps the condition in a biomarker limbus. In this review, we highlight the participation of long non-coding RNAs (lncRNAs) in the regulation of the PD-1/PD-L1 pathway, as well as in the definition of prognostic immune-related signatures in many types of tumors, aiming to shed light on molecules that deserve further investigation for a potential role as biomarkers. We also conducted a bioinformatic analysis to investigate lncRNAs already investigated in PD-1/PDL-1 pathways in other cancer types, considering the TNBC molecular context. In this sense, from the generated data, we evidence here two lncRNAs, UCA1 and HCP5, which have not yet been identified in the context of the tumoral immune response in breast cancer. These candidates can be further explored to verify their use as biomarkers for ICI response. In this article, we present an updated review regarding the use of lncRNA as biomarkers of response to ICI, highlighting the versatility of using these molecules.
Vessel-Guided Mesohepatectomy for Liver Partition and Staged Major Parenchyma-Sparing Hepatectomies with Super-Selective Portal Vein Embolization or Enhanced ALPPS to Achieve R0 Resection for Colorectal Liver Metastases at the Hepatocaval Confluence
Authors: Urbani Lucio , Roffi Nicolò , Moretto Roberto , Signori Stefano , Balestri Riccardo , Rossi Elisabetta , Colombatto Piero , Licitra Gabriella , Leoni Chiara , Martinelli Rita , Meiattini Daniele Anacleto , Bonistalli Emidio , Borelli Beatrice , Antoniotti Carlotta , Masi Gianluca , Rossini Daniele , Boraschi Piero , Donati Francescamaria , Della Pina Maria Clotilde , Lunardi Alessandro , Daviddi Francesco , Crocetti Laura , Tonerini Michele , Gigoni Roberto , Quilici Francesca , Gaeta Raffaele , Turco Francesca , Paolicchi Adriana , Volterrani Duccio , Nardini Vincenzo , Buccianti Piero , Forfori Francesco , Puccini Marco , Cremolini Chiara
Published: September 2023

Background. R0 minor parenchyma-sparing hepatectomy (PSH) is feasible for colorectal liver metastases (CRLM) in contact with hepatic veins (HV) at hepatocaval confluence since HV can be reconstructed, but in the case of contact with the first-order glissonean pedicle (GP), major hepatectomy is mandatory. To pursue an R0 parenchyma-sparing policy, we proposed vessel-guided mesohepatectomy for liver partition (MLP) and eventually combination with liver augmentation techniques for staged major PSH. Methods. We analyzed 15 consecutive vessel-guided MLPs for CRLM at the hepatocaval confluence. Patients had a median of 11 (range: 0–67) lesions with a median diameter of 3.5 cm (range: 0.0–8.0), bilateral in 73% of cases. Results. Grade IIIb or more complications occurred in 13%, median hospital stay was 14 (range: 6–62) days, 90-day mortality was 0%. After a median follow-up of 17.5 months, 1-year OS and RFS were 92% and 62%. In nine (64%) patients, MLP was combined with portal vein embolization (PVE) or ALPPS to perform staged R0 major PSH. Future liver remnant (FLR) volume increased from a median of 15% (range: 7–20%) up to 41% (range: 37–69%). Super-selective PVE was performed in three (33%) patients and enhanced ALPPS (e-ALPPS) in six (66%). In two e-ALPPS an intermediate stage of deportalized liver PSH was necessary to achieve adequate FLR volume. Conclusions. Vessel-guided MLP may transform the liver in a paired organ. In selected cases of multiple bilobar CRLM, to guarantee oncological radicality (R0), major PSH is feasible combining advanced surgical parenchyma sparing with liver augmentation techniques when FLR volume is insufficient.
Role of DNA Methylation Profiles as Potential Biomarkers and Novel Therapeutic Targets in Head and Neck Cancer
Authors: Burkitt Kyunghee
Published: September 2023

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is associated with high mortality. The main reasons for treatment failure are a low rate of early diagnosis, high relapse rates, and distant metastasis with poor outcomes. These are largely due to a lack of diagnostic, prognostic, and predictive biomarkers in HNSCC. DNA methylation has been demonstrated to play an important role in the pathogenesis of HNSCC, and recent studies have also valued DNA methylation as a potential biomarker in HNSCC. This review summarizes the current knowledge on DNA methylation profiles in HPV-positive and HPV-negative HNSCC and how these may contribute to the pathogenesis of HNSCC. It also summarizes the potential value of DNA methylation as a biomarker in the diagnosis, prognosis, and prediction of the response to therapy. With the recent immunotherapy era in head and neck treatment, new strategies to improve immune responses by modulating TIMEs have been intensely investigated in early-phase trials. Therefore, this study additionally summarizes the role of DNA methylation in the regulation of TIMEs and potential predictive immunotherapy response biomarkers. Finally, this study reviews ongoing clinical trials using DNA methylation inhibitors in HNSCC.
The Role of the Dysregulation of Long Non-Coding and Circular RNA Expression in Medulloblastoma: A Systematic Review
Authors: Martinez de Estibariz Ivan , Jakjimovska Anastasija , Illarregi Unai , Martin-Guerrero Idoia , Gutiérrez-Camino Angela , Lopez-Lopez Elixabet , Bilbao-Aldaiturriaga Nerea
Published: September 2023

Medulloblastoma (MB) is the most common malignant brain tumor in childhood. Although recent multi-omic studies have led to advances in MB classification, there is still room for improvement with regard to treatment response and survival. Therefore, identification of new and less invasive biomarkers is needed to refine the diagnostic process and to develop more personalized treatment strategies. In this context, non-coding RNAs (ncRNAs) could be useful biomarkers for MB. In this article, we reviewed the role of two types of ncRNAs, long non-coding (lncRNAs) and circular RNAs (circRNAs), as biomarkers for the diagnosis, subgroup classification, and prognosis of MB. We also reviewed potential candidates with specific functions and mechanisms of action in the disease. We performed a search in PubMed and Scopus using the terms (“long non coding RNAs” OR ”lncRNAs”) and (“circular RNAs” OR ”circRNAs”) AND ”medulloblastoma” to identify biomarker discovery or functional studies evaluating the effects of these ncRNAs in MB. A total of 26 articles met the inclusion criteria. Among the lncRNAs, the tumorigenic effects of the upregulated lnc-IRX3-80 and lnc-LRRC47-78 were the most studied in MB. Among the circRNAs, the upregulation of circSKA3 and its functional impact in MB cell lines were the most consistent results, so this circRNA could be considered a potential biomarker in MB. Additional validation is required for many deregulated lncRNAs and circRNAs; therefore, further studies are warranted.
Optical Genome Mapping Reveals the Complex Genetic Landscape of Myeloma
Authors: Giguère Amélie , Raymond-Bouchard Isabelle , Collin Vanessa , Claveau Jean-Sébastien , Hébert Josée , LeBlanc Richard
Published: September 2023

Fluorescence in situ hybridization (FISH) on enriched CD138 plasma cells is the standard method for identification of clinically relevant genetic abnormalities in multiple myeloma. However, FISH is a targeted analysis that can be challenging due to the genetic complexity of myeloma. The aim of this study was to evaluate the potential of optical genome mapping (OGM) to detect clinically significant cytogenetic abnormalities in myeloma and to provide larger pangenomic information. OGM and FISH analyses were performed on CD138-purified cells of 20 myeloma patients. OGM successfully detected structural variants (SVs) (IGH and MYC rearrangements), copy number variants (CNVs) (17p/TP53 deletion, 1p deletion and 1q gain/amplification) and aneuploidy (gains of odd-numbered chromosomes, monosomy 13) classically expected with myeloma and led to a 30% increase in prognosis yield at our institution when compared to FISH. Despite challenges in the interpretation of OGM calls for CNV and aneuploidy losses in non-diploid genomes, OGM has the potential to replace FISH as the standard of care analysis in clinical settings and to efficiently change how we identify prognostic and predictive markers for therapies in the future. To our knowledge, this is the first study highlighting the feasibility and clinical utility of OGM in myeloma.
Genetic Variants as Predictors of the Success of Colorectal Cancer Treatments
Authors: Garcia-Etxebarria Koldo , Etxart Ane , Barrero Maialen , Nafria Beatriz , Segues Merino Nerea Miren , Romero-Garmendia Irati , Goel Ajay , Franke Andre , D’Amato Mauro , Bujanda Luis
Published: September 2023

Background: Some genetic polymorphisms (SNPs) have been proposed as predictors for different colorectal cancer (CRC) outcomes. This work aims to assess their performance in our cohort and find new SNPs associated with them. Methods: A total of 833 CRC cases were analyzed for seven outcomes, including the use of chemotherapy, and stratified by tumor location and stage. The performance of 63 SNPs was assessed using a generalized linear model and area under the receiver operating characteristic curve, and local SNPs were detected using logistic regressions. Results: In total 26 of the SNPs showed an AUC > 0.6 and a significant association (p < 0.05) with one or more outcomes. However, clinical variables outperformed some of them, and the combination of genetic and clinical data showed better performance. In addition, 49 suggestive (p < 5 × 10−6) SNPs associated with one or more CRC outcomes were detected, and those SNPs were located at or near genes involved in biological mechanisms associated with CRC. Conclusions: Some SNPs with clinical data can be used in our population as predictors of some CRC outcomes, and the local SNPs detected in our study could be feasible markers that need further validation as predictors.
Estrogen Receptor Signaling in Breast Cancer
Authors: Miziak Paulina , Baran Marzena , Błaszczak Ewa , Przybyszewska-Podstawka Alicja , Kałafut Joanna , Smok-Kalwat Jolanta , Dmoszyńska-Graniczka Magdalena , Kiełbus Michał , Stepulak Andrzej
Published: September 2023

Estrogen receptor (ER) signaling is a critical regulator of cell proliferation, differentiation, and survival in breast cancer (BC) and other hormone-sensitive cancers. In this review, we explore the mechanism of ER-dependent downstream signaling in BC and the role of estrogens as growth factors necessary for cancer invasion and dissemination. The significance of the clinical implications of ER signaling in BC, including the potential of endocrine therapies that target estrogens’ synthesis and ER-dependent signal transmission, such as aromatase inhibitors or selective estrogen receptor modulators, is discussed. As a consequence, the challenges associated with the resistance to these therapies resulting from acquired ER mutations and potential strategies to overcome them are the critical point for the new treatment strategies’ development.
Racial and Ethnic Disparities in Gynecologic Carcinosarcoma: A Single-Institution Experience
Authors: Mercado Kristina E. , Badiner Nora M. , Wang Canty , Denham Laura , Unternaehrer Juli J. , Hong Linda J. , Ioffe Yevgeniya J.
Published: September 2023

We aimed to determine the incidence, treatment regimen, and treatment outcomes (including progression-free survival and overall survival) of gynecologic carcinosarcoma, a rare, aggressive, and understudied gynecologic malignancy. This retrospective review included all patients with gynecologic cancers diagnosed and treated at a single tertiary care comprehensive cancer center between January 2012 and May 2021. A total of 2116 patients were eligible for review, of which 84 cases were identified as carcinosarcoma: 66 were uterine (5.2% of uterine cancers), 17 were ovarian (3.6% of ovarian cancers), 1 was cervical (0.28% of cervical cancers), and 1 was untyped. Of the patients, 76.2% presented advanced-stage disease (stage III/IV) at the time of diagnosis. Minority patients were more likely to present with stage III/IV (p < 0.0001). The majority of patients underwent surgical resection followed by systemic chemotherapy with carboplatin and paclitaxel. The median PFS was 7.5 months. Of the patients, 55% were alive 1 year after diagnosis, and 45% were alive at 5 years. In the studied population, minorities were more likely to present with more advanced disease. The rate of gynecologic carcinosarcomas was consistent with historical reports.
Surgical Management of Intrahepatic Cholangiocarcinoma: Quo Vadis
Authors: Moris Dimitrios
Published: September 2023

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignancy related to very high mortality rates [...]
Review of Outcomes after Salvage Surgery for Recurrent Squamous Cell Carcinoma of the Head and Neck
Authors: Hartl Dana M. , Guerlain Joanne , Gorphe Philippe , Kapre Madan , Kapre Gupta Neeti , Saba Nabil F. , Robbins K. Thomas , Ronen Ohad , Rodrigo Juan P. , Strojan Primož , Mäkitie Antti A. , Kowalski Luiz P. , Shah Jatin P. , Ferlito Alfio
Published: September 2023

Surgery with adjuvant chemoradiotherapy or chemoradiotherapy is the mainstay in treatment for advanced stage head and neck squamous cell carcinoma; however, locoregional recurrences are frequent. Salvage surgery could be proposed in selected patients to improve local control, disease-free, and overall survival. Factors for improved disease-free and overall survival in patients treated with salvage surgery include age, tumor location, the initial T stage, HPV status, resection margins, and the time elapsing from the initial treatment. Clinical trials with adjuvant therapies have shown promise after salvage surgery in terms of tolerance and response, but clinical guidelines for using these adjuvant treatments are currently lacking. The aim of this review is to present current knowledge concerning the incidence and management of recurrent head and neck squamous cell carcinoma and current data concerning survival and morbidity after salvage surgery.
Generation of Novel Immunocompetent Mouse Cell Lines to Model Experimental Metastasis of High-Risk Neuroblastoma
Authors: Dhamdhere Mayura R. , Spiegelman Dan V. , Schneper Lisa , Erbe Amy K. , Sondel Paul M. , Spiegelman Vladimir S.
Published: September 2023

NB, being a highly metastatic cancer, is one of the leading causes of cancer-related deaths in children. Increased disease recurrence and clinical resistance in patients with metastatic high-risk NBs (HR-NBs) result in poor outcomes and lower overall survival. However, the paucity of appropriate in vivo models for HR-NB metastasis has limited investigations into the underlying biology of HR-NB metastasis. This study was designed to address this limitation and develop suitable immunocompetent models for HR-NB metastasis. Here, we developed several highly metastatic immunocompetent murine HR-NB cell lines. Our newly developed cell lines show 100% efficiency in modeling experimental metastasis in C57BL6 mice and feature metastasis to the sites frequently observed in humans with HR-NB (liver and bone). In vivo validation demonstrated their specifically gained metastatic phenotype. The in vitro characterization of the cell lines showed increased cell invasion, acquired anchorage-independent growth ability, and resistance to MHC-I induction upon IFN-γ treatment. Furthermore, RNA-seq analysis of the newly developed cells identified a differentially regulated gene signature and an enrichment of processes consistent with their acquired metastatic phenotype, including extracellular matrix remodeling, angiogenesis, cell migration, and chemotaxis. The presented newly developed cell lines are, thus, suitable and promising tools for HR-NB metastasis and microenvironment studies in an immunocompetent system.
Analysis of Artificial Intelligence-Based Approaches Applied to Non-Invasive Imaging for Early Detection of Melanoma: A Systematic Review
Authors: Patel Raj H. , Foltz Emilie A. , Witkowski Alexander , Ludzik Joanna
Published: September 2023

Background: Melanoma, the deadliest form of skin cancer, poses a significant public health challenge worldwide. Early detection is crucial for improved patient outcomes. Non-invasive skin imaging techniques allow for improved diagnostic accuracy; however, their use is often limited due to the need for skilled practitioners trained to interpret images in a standardized fashion. Recent innovations in artificial intelligence (AI)-based techniques for skin lesion image interpretation show potential for the use of AI in the early detection of melanoma. Objective: The aim of this study was to evaluate the current state of AI-based techniques used in combination with non-invasive diagnostic imaging modalities including reflectance confocal microscopy (RCM), optical coherence tomography (OCT), and dermoscopy. We also aimed to determine whether the application of AI-based techniques can lead to improved diagnostic accuracy of melanoma. Methods: A systematic search was conducted via the Medline/PubMed, Cochrane, and Embase databases for eligible publications between 2018 and 2022. Screening methods adhered to the 2020 version of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Included studies utilized AI-based algorithms for melanoma detection and directly addressed the review objectives. Results: We retrieved 40 papers amongst the three databases. All studies directly comparing the performance of AI-based techniques with dermatologists reported the superior or equivalent performance of AI-based techniques in improving the detection of melanoma. In studies directly comparing algorithm performance on dermoscopy images to dermatologists, AI-based algorithms achieved a higher ROC (>80%) in the detection of melanoma. In these comparative studies using dermoscopic images, the mean algorithm sensitivity was 83.01% and the mean algorithm specificity was 85.58%. Studies evaluating machine learning in conjunction with OCT boasted accuracy of 95%, while studies evaluating RCM reported a mean accuracy rate of 82.72%. Conclusions: Our results demonstrate the robust potential of AI-based techniques to improve diagnostic accuracy and patient outcomes through the early identification of melanoma. Further studies are needed to assess the generalizability of these AI-based techniques across different populations and skin types, improve standardization in image processing, and further compare the performance of AI-based techniques with board-certified dermatologists to evaluate clinical applicability.
Physical Activity Level and Quality of Life of Children Treated for Malignancy, Depending on Their Place of Residence: Poland vs. the Czech Republic: An Observational Study
Authors: Kowaluk Aleksandra , Siewierska Katarzyna , Choniawkova Marie , Sedlacek Petr , Kałwak Krzysztof , Malicka Iwona
Published: September 2023

This study aimed to assess the level of physical activity (PA) and quality of life of cancer-treated children, depending on their place of residence (Poland vs. the Czech Republic, where incidence and mortality rates of childhood malignancies are similar). A total of 68 school-age children (7–18 years) undergoing oncological treatment were included in this study. This study used the quality of life questionnaire (KIDSCREEN-10) and the HBSC questionnaire. This study showed statistically significant differences in the level of PA between Polish and Czech children. In Poland, 93.75% of children exhibited no weekly physical effort at the level of moderate to vigorous PA. In the Czech Republic, 69.44% of children engaged in PA lasting at least 60 min per day, or at least 1 day weekly. Physically active children engaging in more frequent effort, at least 60 min daily, reported higher physical performance (rho = 0.41), higher energy levels (rho = 0.41), and less mood disturbance (rho = −0.31). Children with good relationships with parents were more likely to engage in submaximal PA and spend less time on stationary games. Our study showed that an appropriate level of PA improves well-being and quality of life. It is crucial to promote attractive PA programs tailored for cancer-treated children.
The Enigma of Atypical Cartilaginous Tumors: Surgery or Surveillance?
Authors: Leithner Andreas , Smolle Maria Anna
Published: September 2023

During the last 20 years, the treatment of atypical cartilaginous tumors (ACTs) of the long bones has undergone a dramatic change: while these formerly called chondrosarcomas G1 previously led to wide resections and big reconstructions with megaprostheses, today, the use curettage of the lesions and filling the defect e [...]
MAGE-A10 Protein Expression in Advanced High Grade Serous Ovarian Cancer Is Associated with Resistance to First-Line Platinum-Based Chemotherapy
Authors: Lisica Šikić Nataša , Petrić Miše Branka , Tomić Snježana , Spagnol Giulia , Matak Luka , Juretić Antonio , Spagnoli Giulio
Published: September 2023

Ovarian cancer has a dismal prognosis. Standard treatment following surgery relies on platinum-based chemotherapy. However, sizeable percentages of patients are unresponsive. Identification of markers predicting the response to chemotherapy might help select eligible patients and spare non-responding patients from treatment-associated toxicity. Cancer/testis antigens (CTAs) are expressed by healthy germ cells and malignant cells of diverse histological origin. This expression profile identifies them as attractive targets for cancer immunotherapies. We analyzed the correlations between expression of MAGE-A10 and New York esophageal-1 cancer (NY-ESO-1) CTAs at the protein level and the effectiveness of platinum-based chemotherapy in patients with advanced-stage high-grade serous ovarian carcinoma (HGSOC). MAGE-A10 and NY-ESO-1 protein expression was analyzed by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded samples from 93 patients with advanced-stage HGSOC treated at our institutions between January 1996 and December 2013. The correlation between the expression of these markers and response to platinum-based chemotherapy, evaluated according to RECIST 1.1 criteria and platinum sensitivity, measured as platinum-free interval (PFI), progression free (PFS), and overall survival (OS) was explored. The MAGE-A10 protein expression predicted unresponsiveness to platinum-based chemotherapy (p = 0.005), poor platinum sensitivity (p < 0.001), poor PFS (p < 0.001), and OS (p < 0.001). Multivariate analysis identified MAGE-A10 protein expression as an independent predictor of poor platinum sensitivity (p = 0.005) and shorter OS (p < 0.001). Instead, no correlation was observed between the NY-ESO-1 protein expression and response to platinum-based chemotherapy (p = 0.832), platinum sensitivity (p = 0.168), PFS (p = 0.126), and OS (p = 0.335). The MAGE-A10 protein expression reliably identified advanced-stage HGSOC unresponsive to platinum-based chemotherapy. Targeted immunotherapy could represent an important alternative therapeutic option in these cancers.
Prognostic Significance of the Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI) in Patients with Myelofibrosis: A Retrospective Study
Authors: Koster Kira-Lee , Messerich Nora-Medea , Volken Thomas , Cogliatti Sergio , Lehmann Thomas , Graf Lukas , Holbro Andreas , Benz Rudolf , Demmer Izadora , Jochum Wolfram , Rao Tata Nageswara , Silzle Tobias
Published: September 2023

In myelofibrosis, comorbidities (CMs) add prognostic information independently from the Dynamic International Prognostic Scoring System (DIPSS). The Myelodysplastic Syndrome-Specific Comorbidity Index (MDS-CI) offers a simple tool for CM assessment as it is calculable after having performed a careful history and physical examination, a small routine chemistry panel (including creatinine and liver enzymes) and a limited set of functional diagnostics. To assess the prognostic impact of the MDS-CI in addition to the DIPSS and the Mutation-Enhanced International Prognostic Scoring System (MIPSS)-70, we performed a retrospective chart review of 70 MF patients who had not received allogeneic stem cell transplantation (primary MF, n = 51; secondary MF, n = 19; median follow-up, 40 months) diagnosed at our institution between 2000 and 2020. Cardiac diseases (23/70) and solid tumors (12/70) were the most common CMs observed at MF diagnosis. Overall survival (OS) was significantly influenced by the MDS-CI (median OS MDS-CI low (n = 38): 101 months; MDS-CI intermediate (n = 25): 50 months; and high (n = 7): 8 months; p < 0.001). The MDS-CI added prognostic information after inclusion as a categorical variable in a multivariate model together with the dichotomized DIPSS or the dichotomized MIPSS70: MDS-CI high HR 14.64 (95% CI 4.42; 48.48), p = 0.0002, and MDS-CI intermediate HR 1.97 (95% CI 0.96; 4.03), p = 0.065, and MDS-CI high HR 19.65 (95% CI 4.71; 81.95), p < 0.001, and MDS-CI intermediate HR 1.063 (95% CI 0.65; 4.06), p = 0.2961, respectively. The analysis of our small and retrospective MF cohort suggests that the MDS-CI represents a useful tool to identify MF patients with an increased vulnerability due to comorbidities. However, analyses of larger cohorts are necessary to define the value of the MDS-CI as a prognostic tool in comparison with other comorbidity indices.
Prediction of Maxillary Bone Invasion in Hard Palate/Upper Alveolus Cancer: A Multi-Center Retrospective Study
Authors: Choi Nayeon , Jang Jeon Yeob , Kim Min-Ji , Ryu Sung Seok , Jung Young Ho , Jeong Han-Sin
Published: September 2023

Background: maxillary bone invasion (MBI) is not uncommon in hard palate or upper alveolus (HP/UA) cancer; however, there have been relatively few reports about the MBI of HP/UA cancer. Patients and Methods: this was a multi-center retrospective study, enrolling 144 cases of HP/UA cancer. MBI was defined by surgical pathology or radiology follow-up. The multiple prediction models for MBI were developed in total cases and in cases having primary bone resection, using clinical and radiological variables. Results: computerized tomography (CT) alone predicted MBI, with an area under receiver operating curve (AUC) of 0.779 (95% confidence interval (CI) = 0.712–0.847). The AUC was increased in a model that combined tumor dimensions and clinical factors (male sex and nodal metastasis) (0.854 (95%CI = 0.790–0.918)). In patients who underwent 18fluorodeoxyglucose positron emission tomography/CT (PET/CT), the discrimination performance of a model including the maximal standardized uptake value (SUVmax) had an AUC of 0.911 (95%CI = 0.847–0.975). The scoring system using CT finding, tumor dimension, and clinical factors, with/without PET/CT SUVmax clearly distinguished low-, intermediate-, and high-risk groups for MBI. Conclusion: using information from CT, tumor dimension, clinical factors, and the SUVmax value, the MBI of HP/UA cancer can be predicted with a relatively high discrimination performance.
The Potential of Hormonal Therapies for Treatment of Triple-Negative Breast Cancer
Authors: Kirkby Melanie , Popatia Alyanna M. , Lavoie Jessie R. , Wang Lisheng
Published: September 2023

Triple-negative breast cancer (TNBC) is considered one of the most aggressive forms of breast cancer with poor survival rates compared to other breast cancer subtypes. TNBC is characterized by the absence of the estrogen receptor alpha, progesterone receptor, and the human epidermal growth factor receptor 2, limiting those viable treatment options available to patients with other breast cancer subtypes. Furthermore, due to the particularly high heterogeneity of TNBC, conventional treatments such as chemotherapy are not universally effective, leading to drug resistance and intolerable side effects. Thus, there is a pressing need to discover new therapies beneficial to TNBC patients. This review highlights current findings regarding the roles of three steroid hormone receptors, estrogen receptor beta, the androgen receptor, and the glucocorticoid receptor, in the progression of TNBC. In addition, we discussed several ongoing and completed clinical trials targeting these hormone receptors in TNBC patients.
Immobilization of Phospholipase D for Production of Phosphatidylserine by a Pickering Emulsion Strategy
Authors: Sun Hui , Zhang Shujing , Liu Dianqing , Huang Zhiqi , Ge Yuxin , Hou Jiayi , Lu Fuping , Liu Yihan
Published: September 2023

As a natural phospholipid, phosphatidylserine (PS) plays a key role in the food, cosmetic, and pharmaceutical industries. Recently, substantial attention has been focused on the phospholipase D (PLD)-mediated synthesis of PS. However, the application of free PLD is usually limited by high cost, poor reusability, and low stability. In this study, PLD from Streptomyces antibiotics (saPLD) was efficiently immobilized on SiO2 through physical adsorption to develop saPLD@SiO2. The stability of the saPLD@SiO2 was higher than that of the free saPLD over an extensive range of temperature and pH conditions. Furthermore, the PS yield of saPLD@SiO2 was approximately 41% in the first cycles, and still kept 60% of its initial PS yield after 14 cycles. After a 25-day storage period, the saPLD@SiO2 retained 62.5% of its initial activity, while the free saPLD retained only 34.3%, suggesting that saPLD@SiO2 has better stability than free saPLD. A Pickering emulsion was produced by dispersing saPLD@SiO2 in solutions (ethyl propanoate and acetate/acetic acid buffer) using ultrasound. The engineered Pickering emulsion demonstrated excellent catalytic activity, with a 62% PS yield after 6 h, while free saPLD had only 18%. The results indicated that a high-performance and sustainable biocatalysis method was established for the effective synthesis of PS.
Development and Optimization of Air-Electrodes for Rechargeable Zn–Air Batteries
Authors: Nisa Khair Un , da Silva Freitas Williane , Montero Jorge , D’Epifanio Alessandra , Mecheri Barbara
Published: September 2023

Rechargeable Zn–air batteries (ZABs) can play a significant role in the transition to a cleaner and more sustainable energy system due to their high theoretical energy density, high cell voltage, and environmental friendliness. ZAB’s air cathode is the principal determinant in predicting the battery’s overall performance, as it is responsible for catalyzing the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) during the discharging and charging process, respectively. In this work, a detailed optimization study of the architecture of the air cathode was carried out using the benchmark bifunctional oxygen electrocatalyst (Pt/C-RuO2). The air cathode composition and architecture were optimized regarding the choice of the commercial gas diffusion layer (GDL), the effect of hot pressing the catalyst layer (CL), and the optimum pore size of the current collector. The best cathode from this study shows a maximum power density (PDmax) of 167 mW/cm2, with a round trip efficiency and a voltage gap (Egap) of 59.8% and 0.78 V, respectively, indicating the air cathodes preparation approach proposed in this work as a promising strategy for the improvement of the overall performance of ZABs.
PAN/TiO2 Ultrafiltration Membrane for Enhanced BSA Removal and Antifouling Performance
Authors: Xie Yinshan , Wang Xinning , Li Hulin , Wang Tao , Feng Wei , Li Jian
Published: September 2023

Membrane separation has been widely utilized to eliminate pollutants from wastewater. Among them, a polyacrylonitrile (PAN) ultrafiltration (UF) membrane has presented outstanding stability, and distinguished chemical and thermal properties. However, UF membranes inevitably incur fouling issues during their operation procedure caused by contaminant adhesion on the membrane surface, which would restrict the operational efficiency and increase the maintenance cost. The conventional physical and chemical cleaning is not an effective technique to reduce the fouling due to the additional chemical addition and inevitable structure damage. Recently, UF membranes combined with photocatalytic materials are suggested to be a useful approach to conquer the membrane fouling issues. Herein, TiO2 nanoparticles were utilized to blend with a PAN casting solution for fabricating a composite UF membrane via a phase inversion method. With a certain TiO2 addition, the obtained membranes presented an enhancement of hydrophilicity, which could promote the water permeability and antifouling performance. The optimized M3 membrane prepared with 15.0 wt% PAN and 0.6 wt% TiO2 exhibited an excellent water permeability up to 207.0 L m−2 h−1 bar−1 with an outstanding 99.0% BSA rejection and superior antifouling property. In addition, the photocatalytic TiO2 nanoparticles endowed the M3 membrane with a remarkable self-cleaning ability under the UV irradiation. This facile construction method offered new insight to enhance the UF membrane separation performance with an enhanced antifouling ability.
Influence of Extracellular Matrix Components on the Differentiation of Periodontal Ligament Stem Cells in Collagen I Hydrogel
Authors: Ivanov Alexey A. , Kuznetsova Alla V. , Popova Olga P. , Danilova Tamara I. , Latyshev Andrey V. , Yanushevich Oleg O.
Published: September 2023

Regeneration of periodontal tissues requires an integrated approach to the restoration of the periodontal ligament, cementum, and alveolar bone surrounding the teeth. Current strategies in endogenous regenerative dentistry widely use biomaterials, in particular the decellularized extracellular matrix (dECM), to facilitate the recruitment of populations of resident cells into damaged tissues and stimulate their proliferation and differentiation. The purpose of our study was to evaluate the effect of the exogenous components of the extracellular matrix (hyaluronic acid, laminin, fibronectin) on the differentiation of periodontal ligament stem cells (PDLSCs) cultured with dECM (combinations of decellularized tooth matrices and periodontal ligament) in a 3D collagen I hydrogel. The immunohistochemical expression of various markers in PDLSCs was assessed quantitatively and semi-quantitatively on paraffin sections. The results showed that PDLSCs cultured under these conditions for 14 days exhibited phenotypic characteristics consistent with osteoblast-like and odontoblast-like cells. This potential has been demonstrated by the expression of osteogenic differentiation markers (OC, OPN, ALP) and odontogenic markers (DSPP). This phenomenon corresponds to the in vivo state of the periodontal ligament, in which cells at the interface between bone and cementum tend to differentiate into osteoblasts or cementoblasts. The addition of fibronectin to the dECM most effectively induces the differentiation of PDLSCs into osteoblast-like and odontoblast-like cells under 3D culture conditions. Therefore, this bioengineered construct has a high potential for future use in periodontal tissue regeneration.
Astrocytes in Parkinson’s Disease: From Role to Possible Intervention
Authors: Wang Tianyou , Sun Yingqi , Dettmer Ulf
Published: September 2023

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons. While neuronal dysfunction is central to PD, astrocytes also play important roles, both positive and negative, and such roles have not yet been fully explored. This literature review serves to highlight these roles and how the properties of astrocytes can be used to increase neuron survivability. Astrocytes normally have protective functions, such as releasing neurotrophic factors, metabolizing glutamate, transferring healthy mitochondria to neurons, or maintaining the blood–brain barrier. However, in PD, astrocytes can become dysfunctional and contribute to neurotoxicity, e.g., via impaired glutamate metabolism or the release of inflammatory cytokines. Therefore, astrocytes represent a double-edged sword. Restoring healthy astrocyte function and increasing the beneficial effects of astrocytes represents a promising therapeutic approach. Strategies such as promoting neurotrophin release, preventing harmful astrocyte reactivity, or utilizing regional astrocyte diversity may help restore neuroprotection.
The Cell-Autonomous Pro-Metastatic Activities of PD-L1 in Breast Cancer Are Regulated by N-Linked Glycosylation-Dependent Activation of STAT3 and STAT1
Authors: Erlichman Nofar , Meshel Tsipi , Baram Tamir , Abu Raiya Alaa , Horvitz Tamar , Ben-Yaakov Hagar , Ben-Baruch Adit
Published: September 2023

PD-L1 has been characterized as an inhibitory immune checkpoint, leading to the suppression of potential anti-tumor immune activities in many cancer types. In view of the relatively limited efficacy of immune checkpoint blockades against PD-L1 in breast cancer, our recent study addressed the possibility that in addition to its immune-inhibitory functions, PD-L1 promotes the pro-metastatic potential of the cancer cells themselves. Indeed, our published findings demonstrated that PD-L1 promoted pro-metastatic functions of breast cancer cells in a cell-autonomous manner, both in vitro and in vivo. These functions fully depended on the integrity of the S283 intracellular residue of PD-L1. Here, using siRNAs and the S283A-PD-L1 variant, we demonstrate that the cell-autonomous pro-metastatic functions of PD-L1—tumor cell proliferation and invasion, and release of the pro-metastatic chemokine CXCL8—required the activation of STAT3 and STAT1 in luminal A and triple-negative breast cancer cells. The cell-autonomous pro-metastatic functions of PD-L1 were potently impaired upon inhibition of N-linked glycosylation (kifunensine). Site-specific mutants at each of the N-linked glycosylation sites of PD-L1 (N35, N192, N200, and N219) revealed that they were all required for PD-L1-induced pro-metastatic functions to occur; the N219 site was the main regulator of STAT3 and STAT1 activation, with accompanying roles for N192 and N200 (depending on the cell type). Using a T cell-independent mouse system, we found that cells expressing N35A-PD-L1 and N219A-PD-L1 had a significantly lower tumorigenic and metastatic potential than cells expressing WT-PD-L1. TCGA analyses revealed significant associations between reduced survival and high levels of α-mannosidase II (inferring on N-linked glycosylation) in breast cancer patients. These findings suggest that N-linked glycosylation of PD-L1 may be used to screen for patients who are at greater risk of disease progression, and that modalities targeting N-linked glycosylated PD-L1 may lead to the inhibition of its cell-autonomous pro-metastatic functions and to lower tumor progression in breast cancer.
Angiogenic Function of Human Placental Endothelial Cells in Severe Fetal Growth Restriction Is Not Rescued by Individual Extracellular Matrix Proteins
Authors: Sayres Lauren , Flockton Amanda R. , Ji Shuhan , Rey Diaz Carla , Gumina Diane L. , Su Emily J.
Published: September 2023

Severe fetal growth restriction (FGR) is characterized by increased placental vascular resistance resulting from aberrant angiogenesis. Interactions between endothelial cells (ECs) and the extracellular matrix (ECM) are critical to the complex process of angiogenesis. We have previously found that placental stromal abnormalities contribute to impaired angiogenesis in severe FGR. The objective of this research is to better characterize the effect of individual ECM proteins on placental angiogenic properties in the setting of severe FGR. ECs were isolated from human placentae, either control or affected by severe FGR, and subjected to a series of experiments to interrogate the role of ECM proteins on adhesion, proliferation, migration, and apoptosis. We found impaired proliferation and migration of growth-restricted ECs. Although individual substrates did not substantially impact migratory capacity, collagens I, III, and IV partially mitigated proliferative defects seen in FGR ECs. Differences in adhesion and apoptosis between control and FGR ECs were not evident. Our findings demonstrate that placental angiogenic defects that characterize severe FGR cannot be explained by a singular ECM protein, but rather, the placental stroma as a whole. Further investigation of the effects of stromal composition, architecture, stiffness, growth factor sequestration, and capacity for remodeling is essential to better understand the role of ECM in impaired angiogenesis in severe FGR.
Presynaptic Release-Regulating Sphingosine 1-Phosphate 1/3 Receptors in Cortical Glutamatergic Terminals: Adaptations in EAE Mice and Impact of Therapeutic FTY720
Authors: Roggeri Alessandra , Olivero Guendalina , Usai Cesare , Vanmierlo Tim , Pittaluga Anna
Published: September 2023

This study provides evidence of the existence of presynaptic inhibitory sphingosine-1-phosphate receptor 1 (S1P1R) and facilitatory S1P3R in cortical nerve endings (synaptosomes) of healthy mice. The conclusion relies on the findings that (i) the S1P1R agonist CS-2100 (0.1–30 nM) inhibits the 12 mM KCl-evoked glutamate exocytosis (quantified as the release of [3H]D-aspartate) while the S1P3R allosteric agonist CYM-5541 potentiates it and (ii) these effects are inhibited by the S1P1R antagonist Ex 26 (30–300 nM) and the S1P3R antagonist TY-52156 (100–1000 nM), respectively. Confocal microscopy and western blot analysis confirmed the presence of S1P1R and S1P3R proteins in cortical glutamatergic synaptosomes, which were scarcely accessible to biotin in a biotinylation study. Then, we demonstrated that S1P1R and S1P3R densities and their release activity are amplified in cortical synaptosomes of mice suffering from experimental autoimmune encephalomyelitis (EAE), despite receptors maintain their preferential internal distribution. Receptor changes recover following chronic oral therapeutic FTY720 (0.03 mg/Kg/day). These results improve our knowledge of the role of presynaptic release-regulating S1P1Rs and S1P3Rs controlling glutamate transmission in the CNS also unravelling functional adaptations during EAE that recover following chronic FTY720. In a whole, these findings provide new information on the central neuroprotectant activities of FTY720.
Functional Repetitive Neuromuscular Magnetic Stimulation (frNMS) Targeting the Tibialis Anterior Muscle in Children with Upper Motor Neuron Syndrome: A Feasibility Study
Authors: Grosse Leonie , Meuche Anne C. , Parzefall Barbara , Börner Corinna , Schnabel Julian F. , Späh Malina A. , Klug Pia , Sollmann Nico , Klich Luisa , Hösl Matthias , Heinen Florian , Berweck Steffen , Schröder Sebastian A. , Bonfert Michaela V.
Published: September 2023

Non-invasive neurostimulation as an adjunctive intervention to task-specific motor training is an approach to foster motor performance in patients affected by upper motor neuron syndrome (UMNS). Here, we present first-line data of repetitive neuromuscular magnetic stimulation (rNMS) in combination with personalized task-specific physical exercises targeting the tibialis anterior muscle to improve ankle dorsiflexion (functional rNMS (frNMS)). The main objective of this pilot study was to assess the feasibility in terms of adherence to frNMS, safety and practicability of frNMS, and satisfaction with frNMS. First, during 10 training sessions, only physical exercises were performed (study period (SP) A). After a 1 week break, frNMS was delivered during 10 sessions (SPC). Twelve children affected by UMNS (mean age 8.9 ± 1.6 years) adhered to 93% (SPA) and 94% (SPC) of the sessions, and omittance was not related to the intervention itself in any case. frNMS was safe (no AEs reported in 88% of sessions, no AE-related discontinuation). The practicability of and satisfaction with frNMS were high. Patient/caregiver-reported outcomes revealed meaningful benefits on the individual level. The strength of the ankle dorsiflexors (MRC score) clinically meaningfully increased in four participants as spasticity of ankle plantar flexors (Tardieu scores) decreased in four participants after SPC. frNMS was experienced as a feasible intervention for children affected by UMNS. Together with the beneficial effects achieved on the individual level in some participants, this first study supports further real-world, large-scale, sham-controlled investigations to investigate the specific effects and distinct mechanisms of action of frNMS.
Executive Function and Processing Speed in Children Living with Sickle Cell Anemia
Authors: Kelleher Stephanie C. , Kirkham Fenella J. , Hood Anna M.
Published: September 2023

Executive function and processing speed difficulties are observed in children living with sickle cell anemia (SCA). The influence of processing speed on executive function is not well understood. We recruited 59 children living with SCA and 24 matched controls aged 8–18 years between 2010 and 2016 from clinics in the UK. Children completed tests in processing speed and cognitive flexibility, subdomains of executive function. MRI scans were conducted within one year of testing; oxygen saturation was obtained on the day of testing. Hemoglobin levels were obtained from medical records. Caregivers completed the executive function questionnaire. Hierarchical linear regressions found that hemoglobin, oxygen saturation, age, infarct status, and processing speed were not independent predictors for any model. However, for all cognitive flexibility tests, there was a significant interaction between infarct status and processing speed; children without silent cerebral infarction (SCI) with faster processing speed had better cognitive flexibility. Our findings indicate that, when interpreting executive function difficulties, it is important to account for the relationship between SCI status and processing speed. More research is needed to elucidate the mechanisms, but clinically, including executive function testing as part of clinic visits by embedding psychologists within the healthcare team would appear to be a critical step.
Kawasaki Disease, MIS-C and COVID-19
Authors: Huang Ying-Hsien , Kuo Ho-Chang
Published: September 2023

Kawasaki disease (KD) is a form of systemic vasculitis characterized by inflammation of blood vessels throughout the body, and its exact cause remains unknown [...]
Diagnostic Reference Levels in Interventional Pediatric Cardiology: Two-Year Experience in a Tertiary Referral Hospital in Latin America
Authors: Aristizabal Ana M. , Gutiérrez Jaiber A. , Ramirez Emmanuel , Mejía-Quiñones Valentina , Ubeda Carlos , Mosquera Walter Fernando , Mosquera Walter
Published: September 2023

The goal of the present study was to propose the first local diagnostic reference levels (DRLs) for interventional pediatric cardiology procedures in a large hospital in Colombia. The data collection period was from April 2020 to July 2022. The local DRLs were calculated as the 3rd quartile of patient-dose distributions for the kerma-area product (Pka) values. The sample of collected clinical procedures (255) was divided into diagnostic and therapeutic procedures and grouped into five weight and five age bands. The Pka differences found between diagnostic and therapeutic procedures were statistically significant in all weight and age bands, except for the 1–5-year age group. The local DRLs for weight bands were 3.82 Gy·cm2 (<5 kg), 7.39 Gy·cm2 (5–<15 kg), 19.72 Gy·cm2 (15–<30 kg), 28.99 Gy·cm2 (30–<50 kg), and 81.71 Gy·cm2 (50–<80 kg), respectively. For age bands, the DRLs were 3.97 Gy·cm2 (<1 y), 9.94 Gy·cm2 (1–<5 y), 20.82 Gy·cm2 (5–<10 y), 58.00 Gy·cm2 (10–<16 y), and 31.56 Gy·cm2 (<16 y), respectively. In conclusion, when comparing our results with other existing DRL values, we found that they are similar to other centers and thus there is scope to continue optimizing the radiation dose values. This will contribute to establishing national DRLs for Colombia in the near future.