bluuebunny/crossref_metadata_2025 huggingface dataset:
The Hydroxypyridinone Iron Chelator DIBI Reduces Bacterial Load and Inflammation in Experimental Lung Infection
Authors: Zhang Xiyang , Nickerson Rhea , Burton Lauren , Stueck Ashley , Holbein Bruce , Cheng Zhenyu , Zhou Juan , Lehmann Christian
Published: July 2024

Iron plays a critical role in lung infections due to its function in the inflammatory immune response but also as an important factor for bacterial growth. Iron chelation represents a potential therapeutic approach to inhibit bacterial growth and pathologically increased pro-inflammatory mediator production. The present study was designed to investigate the impact of the iron chelator DIBI in murine lung infection induced by intratracheal Pseudomonas aeruginosa (strain PA14) administration. DIBI is a polymer with a polyvinylpyrrolidone backbone containing nine 3-hydroxy-1-(methacrylamidoethyl)-2-methyl-4(1H) pyridinone (MAHMP) residues per molecule and was given by intraperitoneal injection either as a single dose (80 mg/kg) immediately after PA14 administration or a double dose (second dose 4 h after PA14 administration). The results showed that lung NF-κBp65 levels, as well as levels of various inflammatory cytokines (TNFα, IL-1β, IL-6) both in lung tissue and bronchoalveolar lavage fluid (BALF), were significantly increased 24 h after PA14 administration. Single-dose DIBI did not affect the bacterial load or inflammatory response in the lungs or BALF. However, two doses of DIBI significantly decreased bacterial load, attenuated NF-κBp65 upregulation, reduced inflammatory cytokines production, and relieved lung tissue damage. Our findings support the conclusion that the iron chelator, DIBI, can reduce lung injury induced by P. aeruginosa, via its anti-bacterial and anti-inflammatory effects.
A Scalable, Programmable Neural Stimulator for Enhancing Generalizability in Neural Interface Applications
Authors: Yin Meng , Wang Xiao , Zhang Liuxindai , Shu Guijun , Wang Zhen , Huang Shoushuang , Yin Ming
Published: July 2024

Each application of neurostimulators requires unique stimulation parameter specifications to achieve effective stimulation. Balancing the current magnitude with stimulation resolution, waveform, size, and channel count is challenging, leading to a loss of generalizability across broad neural interfaces. To address this, this paper proposes a highly scalable, programmable neurostimulator with a System-on-Chip (SOC) capable of 32 channels of independent stimulation. The compliance voltage reaches up to ±22.5 V. A pair of 8-bit current-mode DACs support independent waveforms for source and sink operations and feature a user-selectable dual range for low-current intraparenchymal microstimulation with a resolution of 4.31 μA/bit, as well as high current stimulation for spinal cord and DBS applications with a resolution of 48.00 μA/bit, achieving a wide stimulation range of 12.24 mA while maintaining high-resolution biological stimulation. A dedicated communication protocol enables full programmable control of stimulation waveforms, effectively improving the range of stimulation parameters. In vivo electrophysiological experiments successfully validate the functionality of the proposed stimulator. This flexible stimulator architecture aims to enhance its generality across a wide range of neural interfaces and will provide more diverse and refined stimulation strategies.
Biosensors for Cancer Biomarkers Based on Mesoporous Silica Nanoparticles
Authors: Mladenović Minja , Jarić Stefan , Mundžić Mirjana , Pavlović Aleksandra , Bobrinetskiy Ivan , Knežević Nikola Ž.
Published: July 2024

Mesoporous silica nanoparticles (MSNs) exhibit highly beneficial characteristics for devising efficient biosensors for different analytes. Their unique properties, such as capabilities for stable covalent binding to recognition groups (e.g., antibodies or aptamers) and sensing surfaces, open a plethora of opportunities for biosensor construction. In addition, their structured porosity offers capabilities for entrapping signaling molecules (dyes or electroactive species), which could be released efficiently in response to a desired analyte for effective optical or electrochemical detection. This work offers an overview of recent research studies (in the last five years) that contain MSNs in their optical and electrochemical sensing platforms for the detection of cancer biomarkers, classified by cancer type. In addition, this study provides an overview of cancer biomarkers, as well as electrochemical and optical detection methods in general.
Blood Vessel Invasion Is an Independent Prognostic Factor in Endometrial Endometrioid Carcinoma Compared to Lymph Vessel Invasion and Myometrial Invasion Pattern
Authors: Eminović Senija , Babarović Emina , Klarić Marko , Fučkar Čupić Dora
Published: July 2024

We studied 115 cases of EEC diagnosed on hysterectomy specimens. Double immunohistochemical staining (D2-40/CD31) was performed in all 115 cases to show LVI and BVI on the same slide. MELF pattern invasion was present in 24/115 (21%) cases. MELF-positive tumors had a higher frequency of LVI than MELF-negative tumors (58% and 23%, respectively); the frequency of BVI was twice as high in MELF-positive tumors in comparison to MELF-negative tumors (25% and 12%, respectively). These differences were significant (p ˂ 0.0001). All tumors with positive BVI also had a concomitant LVI. The presence of MELF invasion had no impact on overall survival, confirming previous studies. 5-year survival rates were almost equal in cases with negative LVSI and cases with positive isolated LVI (98% vs. 97%). However, in cases where BVI was also present, the 5-year survival rate was significantly lower, 63% (p ˂ 0.0001). Furthermore, BVI proved to be an independent prognostic factor for overall survival, disease-free survival, and recurrence in the multivariate analysis. In conclusion, MELF pattern invasion is a good predictor of lymphatic and blood vessel invasion but has no prognostic value. Our results suggest that BVI in EEC has greater clinical value than isolated LVI or myometrial invasion patterns, and the therapeutic approach should be guided by BVI presence. Therefore, we hope this study will promote the routine evaluation of BVI in the context of EEC diagnostic procedures.
The Aberrant Expression of Biomarkers and Risk Prediction for Neoplastic Changes in Barrett’s Esophagus–Dysplasia
Authors: Choi Young , Bedford Andrew , Pollack Simcha
Published: July 2024

Background: Barrett’s esophagus (BE) is a pre-neoplastic condition associated with an increased risk of esophageal adenocarcinoma (EAC). The accurate diagnosis of BE and grading of dysplasia can help to optimize the management of patients with BE. However, BE may be missed and the accurate grading of dysplasia based on a routine histology has a considerable intra- and interobserver variability. Thus, well-defined biomarker testing remains indispensable. The aim of our study was to identify routinely applicable and relatively specific biomarkers for an accurate diagnosis of BE, as well as determining biomarkers to predict the risk of progression in BE–dysplasia. Methods: Retrospectively, we performed immunohistochemistry to test mucin 2(MUC2), trefoil factor 3 (TFF3), p53, p16, cyclin D1, Ki-67, beta-catenin, and minichromosome maintenance (MCM2) in biopsies. Prospectively, to identify chromosomal alterations, we conducted fluorescent in situ hybridization testing on fresh brush samples collected at the time of endoscopy surveillance. Results: We discovered that MUC2 and TFF3 are specific markers for the diagnosis of BE. Aberrant expression, including the loss and strong overexpression of p53, Ki-67, p16, beta-catenin, cyclin D1, and MCM2, was significantly associated with low-grade dysplasia (LGD), high-grade dysplasia (HGD), and EAC histology, with a relatively high risk of neoplastic changes. Furthermore, the aberrant expressions of p53 and p16 in BE-indefinite dysplasia (IND) progressor cohorts predicted the risk of progression. Conclusions: Assessing the biomarkers would be a suitable adjunct to accurate BE histology diagnoses and improve the accuracy of BE–dysplasia grading, thus reducing interobserver variability, particularly of LGD and risk prediction.
New Emerging Chemokine Receptors: CCR5 or CXCR5 on Tumor Is Associated with Poor Response to Chemotherapy and Poor Prognosis in Locally Advanced Triple-Negative Breast Cancer
Authors: Cabioglu Neslihan , Onder Semen , Karatay Hüseyin , Bayram Aysel , Oner Gizem , Tukenmez Mustafa , Muslumanoglu Mahmut , Igci Abdullah , Dinccag Ahmet , Ozmen Vahit , Aydiner Adnan , Saip Pınar , Yavuz Ekrem
Published: July 2024

Background: We aim to investigate any possible associations between chemokine receptor expression and responses to neoadjuvant chemotherapy (NAC) along with outcomes in patients with triple-negative breast cancer (TNBC) with locally advanced disease. Method: Expressions of chemokine receptors were examined immunohistochemically after staining archival tissue of surgical specimens (n = 63) using specific antibodies for CCR5, CCR7, CXCR4, and CXCR5. Results: Patients with high CCR5, CCR7, CXCR4, and CXCR5 expression on tumors and high CXCR4 expression on tumor-infiltrating lymphocytes (TILs) were less likely to have a pathological complete response (pCR) or Class 0-I RCB-Index compared to others. Patients with residual lymph node metastases (ypN-positive), high CCR5TM(tumor), and high CXCR4TM expressions had an increased hazard ratio (HR) compared to others (DFS: HR = 2.655 [1.029–6.852]; DSS: HR = 2.763 [1.008–7.574]), (DFS: HR = 2.036 [0.805–5.148]; DSS: HR = 2.689 [1.020–7.090]), and (DFS: HR = 2.908 [1.080–7.829]; DSS: HR = 2.132 (0.778–5.846)), respectively. However, patients without CXCR5TIL expression had an increased HR compared to those with CXCR5TIL (DFS: 2.838 [1.266–6.362]; DSS: 4.211 [1.770–10.016]). Conclusions: High expression of CXCR4TM and CCR5TM was found to be associated with poor prognosis, and CXCR5TM was associated with poor chemotherapy response in the present cohort with locally advanced TNBC. Our results suggest that patients with TNBC could benefit from a chemokine receptor inhibitor therapy containing neoadjuvant chemotherapy protocols.
Immunological Signatures for Early Detection of Human Head and Neck Squamous Cell Carcinoma through RNA Transcriptome Analysis of Blood Platelets
Authors: Gill Jappreet Singh , Bansal Benu , Poojary Rayansh , Singh Harpreet , Huang Fang , Weis Jett , Herman Kristian , Schultz Brock , Coban Emre , Guo Kai , Mathur Ramkumar
Published: July 2024

Although there has been a reduction in head and neck squamous cell carcinoma occurrence, it continues to be a serious global health concern. The lack of precise early diagnostic biomarkers and postponed diagnosis in the later stages are notable constraints that contribute to poor survival rates and emphasize the need for innovative diagnostic methods. In this study, we employed machine learning alongside weighted gene co-expression network analysis (WGCNA) and network biology to investigate the gene expression patterns of blood platelets, identifying transcriptomic markers for HNSCC diagnosis. Our comprehensive examination of publicly available gene expression datasets revealed nine genes with significantly elevated expression in samples from individuals diagnosed with HNSCC. These potential diagnostic markers were further assessed using TCGA and GTEx datasets, demonstrating high accuracy in distinguishing between HNSCC and non-cancerous samples. The findings indicate that these gene signatures could revolutionize early HNSCC identification. Additionally, the study highlights the significance of tumor-educated platelets (TEPs), which carry RNA signatures indicative of tumor-derived material, offering a non-invasive source for early-detection biomarkers. Despite using platelet and tumor samples from different individuals, our results suggest that TEPs reflect the transcriptomic and epigenetic landscape of tumors. Future research should aim to directly correlate tumor and platelet samples from the same patients to further elucidate this relationship. This study underscores the potential of these biomarkers in transforming early diagnosis and personalized treatment strategies for HNSCC, advocating for further research to validate their predictive and therapeutic potential.
The Impact of Local Control on Overall Survival after Y-90 Selective Internal Radiotherapy of Liver Metastases in Oligometastatic Cancer: A Retrospective Analysis
Authors: Yeakel John , Seyedin Steven N. , Harada Garrett , Hagopian Garo , Mahmood Sharmeen , Bennett Rebecca , Harris Jeremy P. , Abbott Elliot M. , Lindner Sydney , Dayyani Farshid , Sehgal Varun , Kuo Jeffrey V. , Abi-Jaoudeh Nadine
Published: July 2024

Y-90 Selective Internal Radiotherapy (SIRT) is an ablative therapy used for inoperable liver metastasis. The purpose of this investigation was to examine the impact of local control after SIRT on overall survival (OS) in oligometastatic patients. A retrospective, single-institution study identified oligometastatic patients with ≤5 non-intracranial metastases receiving unilateral or bilateral lobar Y-90 SIRT from 2009 to 2021. The primary endpoint was OS defined from Y-90 SIRT completion to the date of death or last follow-up. Local failure was classified as a progressive disease at the target lesion(s) by RECIST v1.1 criteria starting at 3 months after SIRT. With a median follow-up of 15.7 months, 33 patients were identified who had a total of 79 oligometastatic lesions treated with SIRT, with the majority histology of colorectal adenocarcinoma (n = 22). In total, 94% of patients completed the Y-90 lobectomy. Of the 79 individual lesions treated, 22 (27.8%) failed. Thirteen patients received salvage liver-directed therapy following intrahepatic failure; ten received repeat SIRT. Median OS (mOS) was 20.1 months, and 12-month OS was 68.2%. Intralesional failure was associated with worse 1 y OS (52.3% vs. 86.2%, p = 0.004). These results suggest that intralesional failure following Y-90 may be associated with inferior OS, emphasizing the importance of disease control in low-metastatic-burden patients.
Outcome Prediction Using Multi-Modal Information: Integrating Large Language Model-Extracted Clinical Information and Image Analysis
Authors: Sun Di , Hadjiiski Lubomir , Gormley John , Chan Heang-Ping , Caoili Elaine , Cohan Richard , Alva Ajjai , Bruno Grace , Mihalcea Rada , Zhou Chuan , Gulani Vikas
Published: July 2024

Survival prediction post-cystectomy is essential for the follow-up care of bladder cancer patients. This study aimed to evaluate artificial intelligence (AI)-large language models (LLMs) for extracting clinical information and improving image analysis, with an initial application involving predicting five-year survival rates of patients after radical cystectomy for bladder cancer. Data were retrospectively collected from medical records and CT urograms (CTUs) of bladder cancer patients between 2001 and 2020. Of 781 patients, 163 underwent chemotherapy, had pre- and post-chemotherapy CTUs, underwent radical cystectomy, and had an available post-surgery five-year survival follow-up. Five AI-LLMs (Dolly-v2, Vicuna-13b, Llama-2.0-13b, GPT-3.5, and GPT-4.0) were used to extract clinical descriptors from each patient’s medical records. As a reference standard, clinical descriptors were also extracted manually. Radiomics and deep learning descriptors were extracted from CTU images. The developed multi-modal predictive model, CRD, was based on the clinical (C), radiomics (R), and deep learning (D) descriptors. The LLM retrieval accuracy was assessed. The performances of the survival predictive models were evaluated using AUC and Kaplan–Meier analysis. For the 163 patients (mean age 64 ± 9 years; M:F 131:32), the LLMs achieved extraction accuracies of 74%~87% (Dolly), 76%~83% (Vicuna), 82%~93% (Llama), 85%~91% (GPT-3.5), and 94%~97% (GPT-4.0). For a test dataset of 64 patients, the CRD model achieved AUCs of 0.89 ± 0.04 (manually extracted information), 0.87 ± 0.05 (Dolly), 0.83 ± 0.06~0.84 ± 0.05 (Vicuna), 0.81 ± 0.06~0.86 ± 0.05 (Llama), 0.85 ± 0.05~0.88 ± 0.05 (GPT-3.5), and 0.87 ± 0.05~0.88 ± 0.05 (GPT-4.0). This study demonstrates the use of LLM model-extracted clinical information, in conjunction with imaging analysis, to improve the prediction of clinical outcomes, with bladder cancer as an initial example.
Impact of Neoadjuvant Treatment on Body Composition in Patients with Locally Advanced Gastric Cancer
Authors: Juez Luz Divina , Priego Pablo , Cuadrado Marta , Blázquez Luis A. , Sánchez-Picot Silvia , Gil Pablo , Longo Federico , Galindo Julio , Fernández-Cebrián José María , Botella-Carretero José I.
Published: July 2024

Neoadjuvant chemotherapy (NT) followed by radical surgery is the standard treatment for locally advanced gastric cancer (GC). The incidence of sarcopenia in upper gastrointestinal tract malignancies is very high, and it may be increased after NT. This study aimed to evaluate the impact of NT on body composition. A retrospective study of patients with locally advanced GC undergoing gastrectomy who had received NT in a tertiary hospital between 2012 and 2019 was conducted. CT measured the skeletal muscle index, total psoas area, and visceral and subcutaneous adipose tissue before and after NT. Of the 180 gastrectomies for GC, 61 patients received NT. During NT, changes in body composition were observed with a decrease in the skeletal muscle mass index (SMMI −2.5%; p < 0.001), and these changes were significantly greater in men (SMMI −10.55%). Before surgery, patients who received NT presented 15% more sarcopenia than those without NT (p = 0.048). In conclusion, patients with locally advanced gastric cancer who receive NT have significant changes in body composition during chemotherapy. These changes, which are at the expense of a loss of muscle mass, lead to an increased incidence of pre-surgical sarcopenia.
Ablation of Small Liver Metastases Presenting as Foci of Diffusion Restriction on MRI–Results from the Prospective Minimally Invasive Thermal Ablation (MITA) Study
Authors: Wijnen Niek , Bruijnen Rutger C. G. , Thelissen Annelou A. B. , de Jong Hugo W. A. M. , van Leeuwaarde Rachel S. , Hagendoorn Jeroen , Bol Guus M. , Smits Maarten L. J.
Published: July 2024

Purpose: Liver metastases presenting as small hyperintense foci on diffusion-weighted imaging (DWI) pose a therapeutic challenge. Ablation is generally not possible since these lesions are often occult on ultrasound and CT. The purpose of this prospective study was to assess if small liver metastases (≤10 mm) detected on DWI can be successfully localized and ablated with the Hepatic Arteriography and C-Arm CT-Guided Ablation technique (HepACAGA). Materials and Methods: All consecutive patients with small liver metastases (≤10 mm), as measured on DWI, referred for ablation with HepACAGA between 1 January 2021, and 31 October 2023, were included. Re-ablations and ablations concomitant with another local treatment were excluded. The primary outcome was the technical success rate, defined as the intraprocedural detection and subsequent successful ablation of small liver metastases using HepACAGA. Secondary outcomes included the primary and secondary local tumor progression (LTP) rates and the complication rate. Results: A total of 15 patients (26 tumors) were included, with liver metastases from colorectal cancer (73%), neuro-endocrine tumors (15%), breast cancer (8%) and esophageal cancer (4%). All 26 tumors were successfully identified, punctured and ablated (a technical success rate of 100%). After a median follow-up of 9 months, primary and secondary LTP were 4% and 0%, respectively. No complications occurred. Conclusion: In this proof-of-concept study, the HepACAGA technique was successfully used to detect and ablate 100% of small liver metastases identified on DWI with a low recurrence rate and no complications. This technique enables the ablation of subcentimeter liver metastases detected on MRI.
Serial Changes of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma Treated with Atezolizumab Plus Bevacizumab
Authors: Murata Yosuke , Nosaka Takuto , Akazawa Yu , Tanaka Tomoko , Takahashi Kazuto , Naito Tatsushi , Matsuda Hidetaka , Ohtani Masahiro , Nakamoto Yasunari
Published: July 2024

Immune checkpoint inhibitors have promising outcomes in patients with hepatocellular carcinoma (HCC); however, there is no reliable biomarker for predicting disease progression. Circulating tumor cells (CTCs) derived from peripheral blood have attracted attention in monitoring therapeutic efficacy. In this study, CTCs were serially collected from HCC patients undergoing atezolizumab plus bevacizumab (Atezo+Bev), and changes in molecular expression and CTC numbers were analyzed to identify effective biomarkers. Changes in CTC numbers during Atezo+Bev reflected the tumor volume. Targeted RNA sequencing with next-generation sequencing (NGS) revealed that patients with elevated transforming growth factor (TGF)-β signaling molecules had a poorer response, whereas those with elevated apoptosis signaling molecules had a favorable response. In addition, compared with changes in CTC counts, changes in TGF-β signaling molecule expression in CTCs accurately and promptly predicted treatment response. Overall, NGS analysis of CTC-derived RNA showed that changes in TGF-β signaling molecules predict treatment response earlier than changes in CTC counts. These findings suggest that changes in the expression of TGF-β molecules in CTCs could serve as novel biomarkers for the early prediction of therapeutic response in patients with unresectable HCC undergoing Atezo+Bev.
Incident Cancer Risk of Patients with Prevalent Type 2 Diabetes Mellitus in Hungary (Part 2)
Authors: Abonyi-Tóth Zsolt , Rokszin György , Sütő Gábor , Fábián Ibolya , Kiss Zoltán , Jermendy György , Kempler Péter , Lengyel Csaba , Wittmann István , Molnár Gergő A.
Published: July 2024

(1) Background: Among the chronic complications of type 2 diabetes mellitus, cancer has become the leading cause of death in several countries. Our objective was to determine whether prevalent type 2 diabetes mellitus is associated with a higher incidence of cancer. (2) Methods: This study comprised a nationwide analysis conducted in Hungary. The study population was divided into two groups: a type 2 diabetes mellitus group vs. a non-diabetic group. The primary outcome was the risk related to overall cancer incidence; a key secondary outcome was the overall incidence of cancer in distinct study years; and a further outcome was the annual percent changes. (3) Results: The odds ratio related to the overall incidence of cancer was 2.50 (95% confidence interval: 2.46–2.55, p < 0.0001) in patients with diabetes as related to non-diabetic controls. The odds ratio was higher in males than in females [ORmales: 2.76 (2.70–2.82) vs. ORfemales: 2.27 (2.22–2.33), p < 0.05 for male-to-female comparison]. The annual cancer incidence rate declined in non-diabetic controls, but not in patients with diabetes [−1.79% (−2.07–−1.52%), p < 0.0001] vs. −0.50% (−1.12–+0.10%), p = 0.0991]. Several types of cancer showed a decreasing tendency in non-diabetic controls, but not in patients with type 2 diabetes. (4) Conclusions: Type 2 diabetes is associated with a higher risk of cancer. While the cancer incidence decreased for non-diabetic individuals with time, it remained unchanged in patients with T2DM.
Management and Outcome of Recurring Low-Grade Intramedullary Astrocytomas
Authors: Chaskis Elly , Silvestri Martina , Aghakhani Nozar , Parker Fabrice , Knafo Steven
Published: July 2024

Intramedullary astrocytomas (IMAs) are the second most frequent intramedullary tumors in adults. Low-grade IMAs (LG-IMA, WHO grade I and II) carry a better prognosis than high-grade IMAs (HG-IMAs). However, adjuvant treatment of LG-IMAs by radiotherapy (RT) and/or chemotherapy (CT) as well as treatment of tumor recurrences remains controversial. The aim of our study was to evaluate the postoperative outcome of LG-IMAs and the management of recurring tumors. We retrospectively reviewed a series of patients operated on for IMA from 1980 to 2022 in a single neurosurgical department. We retrieved 40 patients who received surgery for intramedullary astrocytomas, including 30 LG-IMAs (22 WHO grade I; 5 WHO grade II; 3 “low-grade”) and 10 HG-IMAs (4 WHO grade III; 5 WHO grade IV; 1 “high-grade”). Of the patients with LG-IMAs, the extent of surgical resection was large (gross or subtotal resection >90%) in 30% of cases. Immediate postoperative radiotherapy and/or chemotherapy was proposed only to patients who underwent biopsy (n = 5), while others were initially followed-up. Over a median follow-up of 59 months (range = 13–376), 16 LG-IMA (53.3%) recurred with a mean delay of 28.5 months after surgery (range = 3–288). These included seven biopsies, five partial resections (PR), four subtotal resections (STR) but no gross total resections (GTR). Progression-free survival for LG-IMAs was 51.9% at 3 years and 35.6% at 5 and 10 years; overall survival was 96.3% at 3 years; 90.9% at 5 years and 81.9% at 10 years. There were no significant differences in terms of OS and PFS between WHO grade I and grade II tumors. However, “large resections” (GTR or STR), as opposed to “limited resections” (PR and biopsies), were associated with both better OS (p = 0.14) and PFS (p = 0.04). The treatment of recurrences consisted of surgery alone (n = 3), surgery with RT and/or CT (n = 2), RT with CT (n = 3), RT alone (n = 2) or CT alone (n = 2). In conclusion, although LG-IMAs are infiltrating tumors, the extent of resection (GTR or STR), but not WHO grading, is the main prognostic factor. The management of recurring tumors is highly variable with no conclusive evidence for either option.
Prevention of Anthracyclines and HER2 Inhibitor-Induced Cardiotoxicity: A Systematic Review and Meta-Analysis
Authors: Sotiropoulou Ioanna Myrto , Manetas-Stavrakakis Nikolaos , Kourek Christos , Xanthopoulos Andrew , Magouliotis Dimitrios , Giamouzis Grigorios , Skoularigis John , Briasoulis Alexandros
Published: July 2024

Background: This meta-analysis and systematic review aim to consolidate evidence on cardiotoxicity prevention and treatment strategies in patients receiving anthracyclines or HER2 receptor inhibitors, vital treatments for breast cancer and hematologic malignancies. By synthesizing existing research, the goal is to provide impactful insights that enhance patient care and outcomes. Methods: Comprehensive research across PubMed, Scopus, EMBASE, and the Cochrane Central Register for Controlled Trials was conducted, selecting clinical trials focusing on cardioprotection in anthracyclines or HER2 inhibitor-treated individuals. Effect sizes were computed using OpenMeta (Analyst), with leave-out meta-analysis to assess potential small study effects. Meta-regression explored treatment duration and sample size effects. Evidence quality for primary outcomes was evaluated using ROB, Robins 2, and Newcastle-Ottawa tools. Results: Twenty -three studies involving a total of 14,652 patients (13,221 adults and 1431 kids) were included in the current systematic review and meta-analysis. The risk of bias and methodological quality of the included studies suggested good and moderate quality. Patients prescribed β-blockers demonstrated a 74% lower likelihood of exhibiting cardiotoxicity symptoms (OR 1.736). Similarly, the use of dexrazoxane was linked to a threefold decrease in cardiac abnormalities risk (OR 2.989), and ACE inhibitor administration showed half the risk compared with the control group (OR 1.956). Conclusions: Through this systematic review and meta-analysis, it was shown that there is a reduction in cardiotoxicity from either anthracyclines or HER2 inhibitors in patients receiving pharmacoprophylaxis.
Antibody-Drug Conjugates in Urothelial Cancer: From Scientific Rationale to Clinical Development
Authors: Kwon Whi-An , Lee Seo-Yeon , Jeong Tae , Kim Hyeon , Lee Min-Kyung
Published: July 2024

Antibody-drug conjugates (ADCs) have been a significant advancement in cancer therapy, particularly for urothelial cancer (UC). These innovative treatments, originally developed for hematological malignancies, use target-specific monoclonal antibodies linked to potent cytotoxic agents. This rational drug design efficiently delivers cancer cell-killing agents to cells expressing specific surface proteins, which are abundant in UC owing to their high antigen expression. UC is an ideal candidate for ADC therapy, as it enhances on-target efficacy while mitigating systemic toxicity. In recent years, considerable progress has been made in understanding the biology and mechanisms of tumor progression in UC. However, despite the introduction of immune checkpoint inhibitors, advanced UC is characterized by rapid progression and poor survival rates. Targeted therapies that have been developed include the anti-nectin 4 ADC enfortumab vedotin and the fibroblast growth factor receptor inhibitor erdafitinib. Enfortumab vedotin has shown efficacy in prospective studies in patients with advanced UC, alone and in combination with pembrolizumab. The anti-Trop-2 ADC sacituzumab govitecan has also demonstrated effectiveness in single-armed studies. This review highlights the mechanism of action of ADCs, their application in mono- and combination therapies, primary mechanisms of resistance, and future perspectives for their clinical use in UC treatment. ADCs have proven to be an increasingly vital component of the therapeutic landscape for urothelial carcinoma, filling a gap in the treatment of this progressive disease.
Total Neoadjuvant Therapy in Localized Pancreatic Cancer: Is More Better?
Authors: Saúde-Conde Rita , El Ghali Benjelloun , Navez Julie , Bouchart Christelle , Van Laethem Jean-Luc
Published: July 2024

Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge in oncology due to its advanced stage upon diagnosis and limited treatment options. Surgical resection, the primary curative approach, often results in poor long-term survival rates, leading to the exploration of alternative strategies like neoadjuvant therapy (NAT) and total neoadjuvant therapy (TNT). While NAT aims to enhance resectability and overall survival, there appears to be potential for improvement, prompting consideration of alternative neoadjuvant strategies integrating full-dose chemotherapy (CT) and radiotherapy (RT) in TNT approaches. TNT integrates chemotherapy and radiotherapy prior to surgery, potentially improving margin-negative resection rates and enabling curative resection for locally advanced cases. The lingering question: is more always better? This article categorizes TNT strategies into six main groups based on radiotherapy (RT) techniques: (1) conventional chemoradiotherapy (CRT), (2) the Dutch PREOPANC approach, (3) hypofractionated ablative intensity-modulated radiotherapy (HFA-IMRT), and stereotactic body radiotherapy (SBRT) techniques, which further divide into (4) non-ablative SBRT, (5) nearly ablative SBRT, and (6) adaptive ablative SBRT. A comprehensive analysis of the literature on TNT is provided for both borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC), with detailed sections for each.
Deconstructing Intratumoral Heterogeneity through Multiomic and Multiscale Analysis of Serial Sections
Authors: Schupp Patrick G. , Shelton Samuel J. , Brody Daniel J. , Eliscu Rebecca , Johnson Brett E. , Mazor Tali , Kelley Kevin W. , Potts Matthew B. , McDermott Michael W. , Huang Eric J. , Lim Daniel A. , Pieper Russell O. , Berger Mitchel S. , Costello Joseph F. , Phillips Joanna J. , Oldham Michael C.
Published: July 2024

Tumors may contain billions of cells, including distinct malignant clones and nonmalignant cell types. Clarifying the evolutionary histories, prevalence, and defining molecular features of these cells is essential for improving clinical outcomes, since intratumoral heterogeneity provides fuel for acquired resistance to targeted therapies. Here we present a statistically motivated strategy for deconstructing intratumoral heterogeneity through multiomic and multiscale analysis of serial tumor sections (MOMA). By combining deep sampling of IDH-mutant astrocytomas with integrative analysis of single-nucleotide variants, copy-number variants, and gene expression, we reconstruct and validate the phylogenies, spatial distributions, and transcriptional profiles of distinct malignant clones. By genotyping nuclei analyzed by single-nucleus RNA-seq for truncal mutations, we further show that commonly used algorithms for identifying cancer cells from single-cell transcriptomes may be inaccurate. We also demonstrate that correlating gene expression with tumor purity in bulk samples can reveal optimal markers of malignant cells and use this approach to identify a core set of genes that are consistently expressed by astrocytoma truncal clones, including AKR1C3, whose expression is associated with poor outcomes in several types of cancer. In summary, MOMA provides a robust and flexible strategy for precisely deconstructing intratumoral heterogeneity and clarifying the core molecular properties of distinct cellular populations in solid tumors.
Transarterial Chemoembolization Treatment Paradigms for Hepatocellular Carcinoma
Authors: Fite Elliott L. , Makary Mina S.
Published: July 2024

Hepatocellular carcinoma (HCC) accounts for 90% of liver cancer cases worldwide and is currently the most quickly increasing cause of cancer-related deaths in the United States. The 5-year survival rate for primary liver cancer is estimated to be below 20%, and HCC mortality is expected to increase by 41% by 2040. Currently, surgical resection is the first-line approach to definitive treatment of early-stage HCC. However, the majority of patients present with late-stage, unresectable disease due to the asymptomatic nature of early HCC. For patients who present with unresectable HCC, locoregional therapies such as transarterial chemoembolization (TACE) represent an alternative approach to HCC treatment. TACE is a minimally invasive, catheter-based technique that allows for targeted delivery of chemotherapy to tumor sites while occluding tumor-feeding blood vessels. In appropriately selected patients, outcomes for TACE therapy have been shown to be more favorable than supportive care or conservative management. The increasing incidence and mortality of HCC, in addition to the late-stage presentation of most HCC patients, demonstrates the need to expand the role of locoregional therapies in the treatment of HCC. TACE represents an appealing approach to HCC management, including disease control, palliation, and potentially curative-intent strategies. In this review, we will describe the current utility of TACE in the treatment of HCC, characterize the outcomes of patients treated with TACE across different HCC stages, and outline future applications of TACE in the treatment paradigm.
Hyperbaric Oxygenation: Can It Be a Novel Supportive Method in Acute Kidney Injury? Data Obtained from Experimental Studies
Authors: Kovacevic Sanjin , Mitovic Nikola , Brkic Predrag , Ivanov Milan , Zivotic Maja , Miloradovic Zoran , Nesovic Ostojic Jelena
Published: July 2024

Despite constant achievements in treatment, acute kidney injury (AKI) remains a significant public health problem and a cause of mortality in the human population. In developed countries, AKI is a significant and frequent hospital complication, especially among patients admitted to intensive care units, where mortality rates can reach up to 50%. In addition, AKI has been implicated as an independent risk factor for the development of chronic kidney disease. Hyperbaric oxygenation (HBO) has been used as a primary or adjunctive therapy for the past 50 years, both in experimental and clinical studies. HBO is a treatment in which the patient is occasionally exposed to 100% oxygen at a pressure greater than atmospheric pressure at sea level. However, despite decades of extensive research, the potentially beneficial effects of this therapeutic approach are still not fully understood, although many potential mechanisms have been proposed, such as antioxidative, anti-inflammatory, anti-apoptotic, etc. Furthermore, the low cost and insignificant adverse events make HBO a potentially important strategy in the prevention and treatment of different diseases. Considering all of this, this review highlights the potential role of HBO in maintaining cellular homeostasis disrupted due to AKI, caused in different experimental models.
Stimuli-Specific Senescence of Primary Human Lung Fibroblasts Modulates Alveolar Stem Cell Function
Authors: Melo-Narváez Maria Camila , Bramey Nora , See Fenja , Heinzelmann Katharina , Ballester Beatriz , Steinchen Carina , Jain Eshita , Federl Kathrin , Hu Qianjiang , Dhakad Deepesh , Behr Jürgen , Eickelberg Oliver , Yildirim Ali Önder , Königshoff Melanie , Lehmann Mareike
Published: July 2024

Aging is the main risk factor for chronic lung diseases (CLDs) including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Accordingly, hallmarks of aging like cellular senescence are increased in these patients in different lung cell types including fibroblasts. However, little is known about the different triggers that induce a senescence phenotype in different disease backgrounds and its role in CLD pathogenesis. Therefore, we characterized senescence in primary human lung fibroblasts (phLF) from control, IPF, or COPD patients at baseline and after exposure to disease-relevant insults (H2O2, bleomycin, TGF-β1) and studied their capacity to support progenitor cell potential in a lung organoid model. Bulk-RNA sequencing revealed that phLF from IPF and COPD activate different transcriptional programs but share a similar senescence phenotype at baseline. Moreover, H2O2 and bleomycin but not TGF-β1 induced senescence in phLF from different disease origins. Exposure to different triggers resulted in distinct senescence programs in phLF characterized by different SASP profiles. Finally, co-culture with bleomycin- and H2O2-treated phLF reduced the progenitor cell potential of alveolar epithelial progenitor cells. In conclusion, phLF from COPD and IPF share a conserved senescence response that varies depending on the insult and impairs alveolar epithelial progenitor capacity ex vivo.
Expanding the Neurological Phenotype of Anderson–Fabry Disease: Proof of Concept for an Extrapyramidal Neurodegenerative Pattern and Comparison with Monogenic Vascular Parkinsonism
Authors: Zedde Marialuisa , Romani Ilaria , Scaravilli Alessandra , Cocozza Sirio , Trojano Luigi , Ragno Michele , Rifino Nicola , Bersano Anna , Gerevini Simonetta , Pantoni Leonardo , Valzania Franco , Pascarella Rosario
Published: July 2024

Anderson–Fabry disease (AFD) is a genetic sphingolipidosis involving virtually the entire body. Among its manifestation, the involvement of the central and peripheral nervous system is frequent. In recent decades, it has become evident that, besides cerebrovascular damage, a pure neuronal phenotype of AFD exists in the central nervous system, which is supported by clinical, pathological, and neuroimaging data. This neurodegenerative phenotype is often clinically characterized by an extrapyramidal component similar to the one seen in prodromal Parkinson’s disease (PD). We analyzed the biological, clinical pathological, and neuroimaging data supporting this phenotype recently proposed in the literature. Moreover, we compared the neurodegenerative PD phenotype of AFD with a classical monogenic vascular disease responsible for vascular parkinsonism and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). A substantial difference in the clinical and neuroimaging features of neurodegenerative and vascular parkinsonism phenotypes emerged, with AFD being potentially responsible for both forms of the extrapyramidal involvement, and CADASIL mainly associated with the vascular subtype. The available studies share some limitations regarding both patients’ information and neurological and genetic investigations. Further studies are needed to clarify the potential association between AFD and extrapyramidal manifestations.
Red Sea Coral Reef Monitoring Site in Sudan after 39 Years Reveals Stagnant Reef Growth, Continuity and Change
Authors: Abdelhamid Sarah , Reinicke Götz B. , Klaus Rebecca , Höhn Johannes , Saad Osama S. , Grenzdörffer Görres
Published: July 2024

Coral reefs off the coast of the Republic of Sudan are still considered to be among the most pristine reefs in the central Red Sea. The complex coastal fringing reefs, offshore banks, and shoals of Dungonab Bay in the north and Sanganeb atoll situated further to the south, about 23 km off the Sudanese mainland coast, were inscribed on the UNESCO World Heritage List in 2016. Due to their remote location and limited access, monitoring of the status of the reefs has been sporadic. Here, we present the results of a repeated large area photomosaic survey (5 m × 5 m plots) on the Sanganeb atoll, first established and surveyed in 1980, and revisited in 1991 and most recently in 2019. The 2019 survey recovered and reinstated the four original monitoring plots. Evaluation of photographic and video records from one photomosaic plot on the seaward slope of the atoll revealed general continuity of the overall community structure and composition over 39 years. Individual colonies of Echinopora gemmacea and Lobophyllia erythraea were recorded in the exact same positions as in the 1980 and 1991 plots. The genera Acropora and Pocillopora remain dominant, although in altered proportions. Shifts in composition were detected at the species level (e.g., increase in Pocillopora verrucosa, Stylophora pistillata, Acropora hemprichii, Dipsastraea pallida, and Echinopora gemmacea, decrease in Acropora cytherea and A. superba), in addition to changes in the extent of uncolonized substrate (e.g., increase from 43.9% in 1980 to 52.2% in 2019), and other scleractinian, hydrozoan, and soft coral living cover. While the temporal resolution only includes three sampling events over 39 years (1980, 1991, 2019), this study presents one of the longest time series of benthic community surveys available for the entire Red Sea. A semi-quantitative estimate of vertical reef growth in the studied test plot indicates a reduction in net accretion rates of more than 80%, from 2.27 to 2.72 cm/yr between 1980 and 1991 to 0.28–0.42 cm/yr between 1991 and 2019. We carefully conclude that the changes observed in the coral community in the plot in 2019 (Acropora–Pocillopora shift, increase in Montipora and calcareous algae) are representative of impacts at the community level, including rising sea surface temperatures and recent bleaching events.
The State of the Art of the Global Distribution of the Invasive Mytilid Species Brachidontes pharaonis (P. Fischer, 1870)
Authors: Battiata Matteo , Curatolo Tiziana , Naser Murtada D. , Sarà Gianluca , Lo Brutto Sabrina
Published: July 2024

The studies on the bioinvasion phenomenon focus mainly on the biological and ecological traits of a species, while scattered literature is addressed to a correct systematic assessment and an updated geographical distribution on the whole. It is noteworthy that non-indigenous species should be monitored on both sides of their range, i.e., towards the front of dispersal and beyond the original range. The backside range boundaries are not often monitored or well delimited; thus, the novel global distribution of an invasive taxon is not often accurately delimitated. A model species for highlighting criticisms about the scarce knowledge on the novel range was chosen. Brachidontes pharaonis is a mussel that has successfully colonised the Mediterranean Sea, following an immigration pathway through the Suez Canal from the Red Sea, presumably from a wider Indo-Pacific area. In this case, the Indo-Pacific boundaries have been overlooked and are still misunderstood due to diverse causes, principally as the synonymy with the congeneric B. variabilis has created confusion in the taxonomic identification. The present review demonstrates that the borders of the B. pharaonis range are still unclear and that the species should be analysed in a wider geographical area. Records of B. pharaonis from Southeast Asia should be treated with caution as this area is out of its range. The Indian and Pacific Oceans host the taxon B. variabilis, composed of two potential cryptic species. Data from the literature highlight the importance of the integrative taxonomic approach to solving various issues concerning the species group complex, morphological variations and cosmopolitan claims of species.
Public Attitudes towards Insect Pollinators in Morocco: Insights from a Pilot Study with Broader Applications
Authors: Sabbahi Rachid , El Abdouni Insafe , Lhomme Patrick , Boubker Omar , Azzaoui Khalil , Hammouti Belkheir , Neffa Mounsef , Hock Virginia
Published: July 2024

This pilot study provides insights into the Moroccan public’s understanding and willingness to engage in insect pollinator preservation, highlighting widespread awareness alongside significant knowledge gaps. The success of biodiversity conservation efforts, especially those aimed at insect pollinators, is greatly enhanced by an informed and committed populace. Understanding public perceptions of insect pollinators is important as it shapes the effectiveness of conservation strategies and their implementation. Although our pilot study does not include every demographic of Moroccan society, it does include an important portion of the populace: educated urban youth. This is a key portion of the population that will be crucial in developing future conservation strategies, especially given the tendency towards increasing urbanization putting cities at the forefront of sustainable development. Our study aimed to assess opinions on insect pollinators, their services, and their declining population numbers in Morocco. We conducted a survey distributed mainly through the media over four months, receiving responses from 301 individuals. The results indicate that the public is aware of decreasing insect pollinator populations and their main threats, and shows a willingness to participate in conservation strategies. However, gaps persist in understanding the roles and ecology of pollinators. While honey bees and bumble bees are well-recognized for their role in pollinating agricultural and wild plants, there is less awareness about other common pollinators such as solitary bees and flies. Additionally, the essential contributions of non-bee pollinators remain widely overlooked. To address these findings, we recommend implementing specialized educational initiatives to increase public understanding of the vital functions of non-bee pollinators in supporting ecosystem services. In order to adopt a more encompassing strategy for the conservation of insect pollinators, upcoming outreach efforts within the national biodiversity strategy should emphasize the contributions made by lesser-known non-bee insect pollinators and strive to engage sectors of the population currently less involved in pollinator conservation. However, while this pilot study provides valuable insights, the sample size limits the generalizability of these conclusions. Future research with larger and more diverse samples would be beneficial to validate and expand upon these findings in order to provide a more comprehensive understanding of all areas of public perception and engagement in pollinator conservation in Morocco. Expanding sampling to include older, less educated, and less urban demographics would strengthen these initial insights and broaden their application, especially beyond urban attitudes.