bluuebunny/crossref_metadata_2025 huggingface dataset:
First-Line Chemoimmunotherapy versus Sequential Platinum-Based Chemotherapy Followed by Immunotherapy in Patients with Non-Small Cell Lung Cancer with ≤49% Programmed Death-Ligand 1 Expression: A Real-World Multicenter Retrospective Study
Authors: Tanimura Keiko , Takeda Takayuki , Kataoka Nobutaka , Yoshimura Akihiro , Nakanishi Kentaro , Yamanaka Yuta , Yoshioka Hiroshige , Honda Ryoichi , Uryu Kiyoaki , Fukui Mototaka , Chihara Yusuke , Takei Shota , Kawachi Hayato , Yamada Tadaaki , Tamiya Nobuyo , Okura Naoko , Yamada Takahiro , Murai Junji , Shiotsu Shinsuke , Kurata Takayasu , Takayama Koichi
Published: October 2023

Background: The long overall survival (OS) observed among patients with non-small cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression in chemoimmunotherapy (CIT) groups in previous phase III trials suggests the limited efficacy of CIT among the subgroup with ≤49% PD-L1 expression on tumor cells. Hence, sequential treatment with first-line platinum-based chemotherapy followed by second-line immune checkpoint inhibitor treatment (SEQ) is an option. This study examined whether first-line CIT would provide better outcomes than SEQ in patients with advanced NSCLC with ≤49% PD-L1 expression. Methods: This retrospective study evaluated patients with untreated NSCLC who received first-line CIT or SEQ at nine hospitals in Japan. OS, progression-free survival (PFS), PFS-2 (the time from first-line treatment to progression to second-line treatment or death), and other related outcomes were evaluated between the CIT and SEQ groups. Results: Among the 305 enrolled patients, 234 eligible patients were analyzed: 165 in the CIT group and 69 in the SEQ group. The COX proportional hazards model suggested a significant interaction between PD-L1 expression and OS (p = 0.006). OS in the CIT group was significantly longer than that in the SEQ group in the 1–49% PD-L1 expression subgroup but not in the <1% PD-L1 expression subgroup. Among the subgroup with 1–49% PD-L1 expression, the CIT group exhibited longer median PFS than the SEQ group (CIT: 9.3 months (95% CI: 6.7–14.8) vs. SEQ:5.5 months (95% CI: 4.5–6.1); p < 0.001), while the median PFS in the CIT group was not statistically longer than the median PFS-2 in the SEQ group (p = 0.586). There was no significant difference between the median PFS in the CIT and SEQ groups among the <1% PD-L1 expression subgroup (p = 0.883); the median PFS-2 in the SEQ group was significantly longer than the median PFS in the CIT group (10.5 months (95% CI: 5.9–15.3) vs. 6.4 months (95% CI: 4.9–7.5); p = 0.024). Conclusions: CIT is recommended for patients with NSCLC with 1–49% PD-L1 expression because it significantly improved OS and PFS compared to SEQ. CIT had limited benefits in patients with <1% PD-L1 expression, and the median PFS-2 in the SEQ group was significantly longer than the median PFS in the CIT group. These findings will help physicians select the most suitable treatment option for patients with NSCLC, considering PD-L1 expressions.
Apparent Diffusion Coefficient Metrics to Differentiate between Treatment-Related Abnormalities and Tumor Progression in Post-Treatment Glioblastoma Patients: A Retrospective Study
Authors: van den Elshout Rik , Herings Siem D. A. , Mannil Manoj , Gijtenbeek Anja M. M. , ter Laan Mark , Smeenk Robert J. , Meijer Frederick J. A. , Scheenen Tom W. J. , Henssen Dylan J. H. A.
Published: October 2023

Distinguishing treatment-related abnormalities (TRA) from tumor progression (TP) in glioblastoma patients is a diagnostic imaging challenge due to the identical morphology of conventional MR imaging sequences. Diffusion-weighted imaging (DWI) and its derived images of the apparent diffusion coefficient (ADC) have been suggested as diagnostic tools for this problem. The aim of this study is to determine the diagnostic accuracy of different cut-off values of the ADC to differentiate between TP and TRA. In total, 76 post-treatment glioblastoma patients with new contrast-enhancing lesions were selected. Lesions were segmented using a T1-weighted, contrast-enhanced scan. The mean ADC values of the segmentations were compared between TRA and TP groups. Diagnostic accuracy was compared by use of the area under the curve (AUC) and the derived sensitivity and specificity values from cutoff points. Although ADC values in TP (mean = 1.32 × 10−3 mm2/s; SD = 0.31 × 10−3 mm2/s) were significantly different compared to TRA (mean = 1.53 × 10−3 mm2/s; SD = 0.28 × 10−3 mm2/s) (p = 0.003), considerable overlap in their distributions exists. The AUC of ADC values to distinguish TP from TRA was 0.71, with a sensitivity and specificity of 65% and 70%, respectively, at an ADC value of 1.47 × 10−3 mm2/s. These findings therefore indicate that ADC maps should not be used in discerning between TP and TRA at a certain timepoint without information on temporal evolution.
Local Recurrence following Radiological Complete Response in Patients Treated with Subsegmental Balloon-Occluded Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma
Authors: Gwon Dong Il , Kim Gun Ha , Chu Hee Ho , Kim Jin Hyoung , Ko Gi-Young , Yoon Hyun-Ki
Published: October 2023

The aim of this study was to determine the local recurrence (LR) rate and identify factors associated with LR in patients who achieve a radiological complete response (CR) after undergoing balloon-occluded transcatheter arterial chemoembolization (B-TACE) for hepatocellular carcinoma (HCC). From November 2017 to September 2021, 60 patients (44 men, 16 women; mean age, 63.5 years; range, 39–82 years) with 72 HCCs (mean diameter, 31 mm; range, 10–50 mm) who underwent subsegmental B-TACE were included in this retrospective study. Radiological and clinical evaluation of oily subsegmentectomy, defined as radiological CR of the HCC and peritumoral parenchymal necrosis, was performed. The CR rate was 97.2% (70 of 72 HCCs) at first follow-up (mean, 41 days; range, 14–110 days). Overall, 13 HCCs (19.7%) demonstrated LR at a mean of 29.8 months (range, 3–63 months) and cumulative LR rates were 1.5% 14.2% 21%, 21%, and 21% at 6, 12, 24, 36, and 48 months, respectively. In 28 (38.9%) of 72 HCCs, oily subsegmentectomy was achieved, tumor markers were normalized, and LR did not occur. The oily subsegmentectomy-positive group had a significantly lower LR rate than the oily subsegmentectomy-negative group (p = 0.001). Age ≥65 years (adjusted hazard ration (HR), 0.124; 95% confidence interval (CI), 0.037–0.412; p < 0.001) and peripheral location (adjusted HR, 0.112; 95% CI, 0.046–0.272; p < 0.001) were independent predictive factors of LR. Subsegmental B-TACE can be an effective method with a high initial CR rate and low LR incidence. Oily subsegmentectomy can be considered as an index of successful treatment because it did not demonstrate any LR.
Artificial Intelligence Reveals Distinct Prognostic Subgroups of Muscle-Invasive Bladder Cancer on Histology Images
Authors: Eminaga Okyaz , Leyh-Bannurah Sami-Ramzi , Shariat Shahrokh F. , Krabbe Laura-Maria , Lau Hubert , Xing Lei , Abbas Mahmoud
Published: October 2023

Muscle-invasive bladder cancer (MIBC) is a highly heterogeneous and costly disease with significant morbidity and mortality. Understanding tumor histopathology leads to tailored therapies and improved outcomes. In this study, we employed a weakly supervised learning and neural architecture search to develop a data-driven scoring system. This system aimed to capture prognostic histopathological patterns observed in H&E-stained whole-slide images. We constructed and externally validated our scoring system using multi-institutional datasets with 653 whole-slide images. Additionally, we explored the association between our scoring system, seven histopathological features, and 126 molecular signatures. Through our analysis, we identified two distinct risk groups with varying prognoses, reflecting inherent differences in histopathological and molecular subtypes. The adjusted hazard ratio for overall mortality was 1.46 (95% CI 1.05–2.02; z: 2.23; p = 0.03), thus identifying two prognostic subgroups in high-grade MIBC. Furthermore, we observed an association between our novel digital biomarker and the squamous phenotype, subtypes of miRNA, mRNA, long non-coding RNA, DNA hypomethylation, and several gene mutations, including FGFR3 in MIBC. Our findings underscore the risk of confounding bias when reducing the complex biological and clinical behavior of tumors to a single mutation. Histopathological changes can only be fully captured through comprehensive multi-omics profiles. The introduction of our scoring system has the potential to enhance daily clinical decision making for MIBC. It facilitates shared decision making by offering comprehensive and precise risk stratification, treatment planning, and cost-effective preselection for expensive molecular characterization.
A Phase II Study of Osimertinib in Patients with Advanced-Stage Non-Small Cell Lung Cancer following Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) Therapy with EGFR and T790M Mutations Detected in Plasma Circulating Tumour DNA (PLASMA Study)
Authors: Ang Yvonne L. E. , Zhao Xiaotian , Reungwetwattana Thanyanan , Cho Byoung-Chul , Liao Bin-Chi , Yeung Rebecca , Loong Herbert H. , Kim Dong-Wan , Yang James Chih-Hsin , Lim Sun Min , Ahn Myung-Ju , Lee Se-Hoon , Suwatanapongched Thitiporn , Kongchauy Kanchaporn , Ou Qiuxiang , Yu Ruoying , Tai Bee Choo , Goh Boon Cher , Mok Tony S. K. , Soo Ross A.
Published: October 2023

Epidermal growth factor receptor (EGFR) T790M mutations drive resistance in 50% of patients with advanced non-small cell lung cancer (NSCLC) who progress on first/second generation (1G/2G) EGFR tyrosine kinase inhibitors (TKIs) and are sensitive to Osimertinib. Tissue sampling is the gold-standard modality of T790M testing, but it is invasive. We evaluated the efficacy of Osimertinib in patients with EGFR mutant NSCLC and T790M in circulating tumour DNA (ctDNA). PLASMA is a prospective, open-label, multicentre single-arm Phase II study. Patients with advanced NSCLC harbouring sensitizing EGFR and T790M mutations in plasma at progression from ≥one 1G/2G TKI were treated with 80 mg of Osimertinib daily until progression. The primary endpoint was the objective response rate (ORR); the secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and toxicities. Plasma next-generation sequencing was performed to determine Osimertinib resistance mechanisms and assess serial ctDNA. A total of 110 patients from eight centres in five countries were enrolled from 2017 to 2019. The median follow-up duration was 2.64 (IQR 2.44–3.12) years. The ORR was 50.9% (95% CI 41.2–60.6) and the DCR was 84.5% (95% CI 76.4–90.7). Median PFS was 7.4 (95% CI 6.0–9.3) months; median OS was 1.63 (95% CI 1.35–2.16) years. Of all of the patients, 76% had treatment-related adverse events (TRAEs), most commonly paronychia (22.7%); 11% experienced ≥ Grade 3 TRAEs. The ctDNA baseline load and dynamics were prognostic. Osimertinib is active in NSCLC harbouring sensitizing EGFR and T790M mutations in ctDNA testing post 1G/2G TKIs.
International Variations in Surgical Morbidity and Mortality Post Gynaecological Oncology Surgery: A Global Gynaecological Oncology Surgical Outcomes Collaborative Led Study (GO SOAR1)
Authors: Gaba Faiza , Ash Karen , Blyuss Oleg , Bizzarri Nicolò , Kamfwa Paul , Saiz Allison , Cibula David ,   GO SOAR Collaborators
Published: October 2023

Gynaecological malignancies affect women in low and middle income countries (LMICs) at disproportionately higher rates compared with high income countries (HICs) with little known about variations in access, quality, and outcomes in global cancer care. Our study aims to evaluate international variation in post-operative morbidity and mortality following gynaecological oncology surgery between HIC and LMIC settings. Study design consisted of a multicentre, international prospective cohort study of women undergoing surgery for gynaecological malignancies (NCT04579861). Multilevel logistic regression determined relationships within three-level nested-models of patients within hospitals/countries. We enrolled 1820 patients from 73 hospitals in 27 countries. Minor morbidity (Clavien–Dindo I–II) was 26.5% (178/672) and 26.5% (267/1009), whilst major morbidity (Clavien–Dindo III–V) was 8.2% (55/672) and 7% (71/1009) for LMICs/HICs, respectively. Higher minor morbidity was associated with pre-operative mechanical bowel preparation (OR = 1.474, 95%CI = 1.054–2.061, p = 0.023), longer surgeries (OR = 1.253, 95%CI = 1.066–1.472, p = 0.006), greater blood loss (OR = 1.274, 95%CI = 1.081–1.502, p = 0.004). Higher major morbidity was associated with longer surgeries (OR = 1.37, 95%CI = 1.128–1.664, p = 0.002), greater blood loss (OR = 1.398, 95%CI = 1.175–1.664, p ≤ 0.001), and seniority of lead surgeon, with junior surgeons three times more likely to have a major complication (OR = 2.982, 95%CI = 1.509–5.894, p = 0.002). Of all surgeries, 50% versus 25% were performed by junior surgeons in LMICs/HICs, respectively. We conclude that LMICs and HICs were associated with similar post-operative major morbidity. Capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention.
Modulatory Properties of Aloe secundiflora’s Methanolic Extracts on Targeted Genes in Colorectal Cancer Management
Authors: Macharia John M. , Varjas Timea , Mwangi Ruth W. , Káposztás Zsolt , Rozmann Nóra , Pintér Márton , Wagara Isabel N. , Raposa Bence L.
Published: October 2023

Colon tumors have a very complicated and poorly understood pathogenesis. Plant-based organic compounds might provide a novel source for cancer treatment with a sufficient novel mode of action. The objective of this study was to analyze and evaluate the efficacy of Aloe secundiflora’s (AS) methanolic extracts on the expression of CASPS9, 5-LOX, Bcl2, Bcl-xL, and COX-2 in colorectal cancer (CRC) management. Caco-2 cell lines were used in the experimental study. In the serial exhaustive extraction (SEE) method, methanol was utilized as the extraction solvent. Upon treatment of CASPS9 with the methanolic extracts, the expression of the genes was progressively upregulated, thus, dose-dependently increasing the rate of apoptosis. On the other hand, the expressions of 5-LOX, Bcl2, and Bcl-xL were variably downregulated in a dose-dependent manner. This is a unique novel study that evaluated the effects of AS methanolic extracts in vitro on CRC cell lines using different dosage concentrations. We, therefore, recommend the utilization of AS and the application of methanol as the extraction solvent of choice for maximum modulatory benefits in CRC management. In addition, we suggest research on the specific metabolites in AS involved in the modulatory pathways that suppress the development of CRC and potential metastases.
Evening Primrose Extract Modulates TYMS Expression via SP1 Transcription Factor in Malignant Pleural Mesothelioma
Authors: Chmielewska-Kassassir Małgorzata , Sobierajska Katarzyna , Ciszewski Wojciech M. , Kryczka Jakub , Zieleniak Andrzej , Wozniak Lucyna A.
Published: October 2023

Purpose: To determine the mechanism of EPE in downregulating TYMS in MPM cancer. Methods: The TYMS mRNA expression with epithelial-to-mesenchymal transition biomarkers and nuclear factor SP1 was assessed using the GEO database in a data set of MPM patients (GSE51024). Invasive MPM cell lines were in vitro models for the investigation of TYMS expression after EPE treatment. The tyms promoter SP1 binding sequences were determined using Genomatix v 3.4 software Electrophoretic mobility shift and dual-luciferase reporter assays revealed specific SP1 motifs in the interaction of EPE and reference compounds. Chromatin immunoprecipitation and Re-ChIP were used for the co-occupancy study. Results: In MPM patients, a positive correlation of overexpressed TYMS with mesenchymal TWIST1, FN1 and N-cadherin was observed. EPE and its major components, gallic and ellagic acid (GA and EA, respectively), downregulated TYMS in invasive MPM cells by interacting with particular SP1 motifs on the tyms promoter. The luciferase constructs confirmed the occupation of two SP1 regulatory regions critical for the promotion of TYMS expression. Both EPE and reference standards influenced SP1 translocation into the nucleus. Conclusion: EPE components reduced TYMS expression by occupation of SP1 motifs on the tyms promoter and reversed the EMT phenotype of invasive MPM cells. Further in-depth analysis of the molecular docking of polyphenol compounds with SP1 regulatory motifs is required.
Increased Risk of Renal Malignancy in Patients with Moderate to Severe Atopic Dermatitis
Authors: Oh Jongwook , Oh Hyun Ju , Han Kyung-Do , Gee Heon Yung , Lee Ji Hyun
Published: October 2023

Background: Evidence for an association between atopic dermatitis (AD) and cancer is still insufficient. In particular, the association between the risk of renal malignancy and the severity of AD has not been thoroughly investigated. Objective: To investigate the risk of renal malignancy and determine the association between AD severity and cancer risk using data from the Korean National Health Insurance Service (KNHIS) database. Methods: We performed a population-based cohort study using the National Health Claims database from the NHIS in Korea. Results: We found a statistically significant association between AD and overall malignancy (for mild AD, hazard ratio (HR): 1.061, 95% confidence interval (CI): 1.006–1.118; for moderate to severe AD, HR: 1.061, 95% CI: 1.014–1.11) compared with the no AD group. The moderate to severe AD group showed a significantly increased risk for renal malignancy (adjusted HR: 1.533, 95% CI: 1.209–1.944) compared with the no AD group. Limitations: Patient inclusion is solely based on diagnostic codes. We had no data about drug use, genetic factors, or other medical history that could affect the cancer risk. Conclusion: In our large population-based cohort study, moderate to severe AD was associated with increased risk of renal malignancy. Regular check-ups for renal malignancy are recommended in this population.
EAU Biochemical Recurrence Risk Classification and PSA Kinetics Have No Value for Patient Selection in PSMA-Radioguided Surgery (PSMA-RGS) for Oligorecurrent Prostate Cancer
Authors: Falkenbach Fabian , Ambrosini Francesca , Tennstedt Pierre , Eiber Matthias , Heck Matthias M. , Preisser Felix , Graefen Markus , Budäus Lars , Koehler Daniel , Knipper Sophie , Maurer Tobias
Published: October 2023

Objective: To assess the influence of biochemical recurrence (BCR) risk groups and PSA kinetics on the outcomes of radioguided surgery against prostate-specific membrane antigen (PSMA-RGS). Currently, neither BCR risk group nor PSA doubling time (PSA-DT), or PSA velocity (PSA-V) are actively assigned or relevant for counseling prior to PSMA-RGS. Methods: We retrospectively analyzed PSMA-RGS cases for oligorecurrent prostate cancer between 2014 and 2023. BCR risk groups, PSA-DT, and PSA-V were analyzed as predictors for complete biochemical response (cBR, PSA < 0.2 ng/mL), BCR-free, and therapy-free survival (BCRFS, TFS). Results: Of 374 included patients, only 21/374 (6%) and 201/374 (54%) were classified as low- and high-risk BCR (no group assignment possible in 152/374, 41%). A total of 13/21 (62%) patients with low- and 120/201 (60%) with high-risk BCR achieved cBR (p = 1.0). BCR classification was no predictor for BCRFS (HR:1.61, CI: 0.70–3.71, p = 0.3) or subsequent TFS (HR:1.07, CI: 0.46–2.47, p = 0.9). A total of 47/76 (62%) patients with PSA-DT ≤ 6 mo and 50/84 (60%) with PSA-DT > 6 mo achieved cBR (p = 0.4). PSA-DT was not associated with cBR (OR: 0.99, CI: 0.95–1.03, p = 0.5), BCRFS (HR: 1.00, CI: 0.97–1.03, p = 0.9), or TFS (HR: 1.02, CI: 0.99–1.04, p = 0.2). Consistent negative findings were recorded for PSA-V. Conclusions: The BCR risk groups and PSA kinetics do not predict the oncological success of PSMA-RGS performed at low absolute PSA values. Indolent low-risk BCR is rarely treated by PSMA-RGS.
Resistance of Lung Cancer to EGFR-Specific Kinase Inhibitors: Activation of Bypass Pathways and Endogenous Mutators
Authors: Marrocco Ilaria , Yarden Yosef
Published: October 2023

Epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitors (TKIs) have changed the landscape of lung cancer therapy. For patients who are treated with the new TKIs, the current median survival exceeds 3 years, substantially better than the average 20 month survival rate only a decade ago. Unfortunately, despite initial efficacy, nearly all treated patients evolve drug resistance due to the emergence of either new mutations or rewired signaling pathways that engage other receptor tyrosine kinases (RTKs), such as MET, HER3 and AXL. Apparently, the emergence of mutations is preceded by a phase of epigenetic alterations that finely regulate the cell cycle, bias a mesenchymal phenotype and activate antioxidants. Concomitantly, cells that evade TKI-induced apoptosis (i.e., drug-tolerant persister cells) activate an intrinsic mutagenic program reminiscent of the SOS system deployed when bacteria are exposed to antibiotics. This mammalian system imbalances the purine-to-pyrimidine ratio, inhibits DNA repair and boosts expression of mutation-prone DNA polymerases. Thus, the net outcome of the SOS response is a greater probability to evolve new mutations. Deeper understanding of the persister-to-resister transformation, along with the development of next-generation TKIs, EGFR-specific proteolysis targeting chimeras (PROTACs), as well as bispecific antibodies, will permit delaying the onset of relapses and prolonging survival of patients with EGFR+ lung cancer.
Limbal Epithelial Stem Cells in the Diabetic Cornea
Authors: Nureen Lamia , Di Girolamo Nick
Published: October 2023

Continuous replenishment of the corneal epithelium is pivotal for maintaining optical transparency and achieving optimal visual perception. This dynamic process is driven by limbal epithelial stem cells (LESCs) located at the junction between the cornea and conjunctiva, which is otherwise known as the limbus. In patients afflicted with diabetes, hyperglycemia-induced impairments in corneal epithelial regeneration results in persistent epithelial and other defects on the ocular surface, termed diabetic keratopathy (DK), which progressively diminish vision and quality of life. Reports of delayed corneal wound healing and the reduced expression of putative stem cell markers in diabetic relative to healthy eyes suggest that the pathogenesis of DK may be associated with the abnormal activity of LESCs. However, the precise role of these cells in diabetic corneal disease is poorly understood and yet to be comprehensively explored. Herein, we review existing literature highlighting aberrant LESC activity in diabetes, focusing on factors that influence their form and function, and emerging therapies to correct these defects. The consequences of malfunctioning or depleted LESC stocks in DK and limbal stem cell deficiency (LSCD) are also discussed. These insights could be exploited to identify novel targets for improving the management of ocular surface complications that manifest in patients with diabetes.
Mammalian Models in Alzheimer’s Research: An Update
Authors: Sharma Himadri , Chang Keun-A , Hulme John , An Seong Soo A.
Published: October 2023

A form of dementia distinct from healthy cognitive aging, Alzheimer’s disease (AD) is a complex multi-stage disease that currently afflicts over 50 million people worldwide. Unfortunately, previous therapeutic strategies developed from murine models emulating different aspects of AD pathogenesis were limited. Consequently, researchers are now developing models that express several aspects of pathogenesis that better reflect the clinical situation in humans. As such, this review seeks to provide insight regarding current applications of mammalian models in AD research by addressing recent developments and characterizations of prominent transgenic models and their contributions to pathogenesis as well as discuss the advantages, limitations, and application of emerging models that better capture genetic heterogeneity and mixed pathologies observed in the clinical situation.
Gene Expression Analyses in Models of Rosiglitazone-Induced Physiological and Pathological Mineralization Identify Novel Targets to Improve Bone and Vascular Health
Authors: Bruedigam Claudia , Leeuwen Johannes P. T. M. van , Peppel Jeroen van de
Published: October 2023

Clinical studies revealed detrimental skeletal and vascular effects of the insulin sensitizer rosiglitazone. We have shown earlier that rosiglitazone accelerates osteoblast differentiation from human mesenchymal stem cells (hMSC) at the expense of increased oxidative stress and cell death. In calcifying human vascular cells, rosiglitazone stimulates pathological mineralization, an effect diminished by the antioxidant resveratrol. Here, we aimed to elucidate transcriptional networks underlying the rosiglitazone-enhanced mineralization phenotype. We performed genome-wide transcriptional profiling of osteogenic hMSCs treated with rosiglitazone for short-term periods of 1 up to 48 h during the first two days of differentiation, a phase that we show is sufficient for rosiglitazone stimulation of mineralization. Microarray-based mRNA expression analysis revealed 190 probes that were differently expressed in at least one condition compared to vehicle-treated control. This rosiglitazone gene signature contained well-known primary PPAR targets and was also endogenously regulated during osteogenic hMSC differentiation and osteoblast-like differentiation of vascular smooth muscle cells (VSMCs) into calcifying vascular cells (CVCs). Comparative analysis revealed rosiglitazone targets that were commonly enriched in osteoblasts and CVCs or specifically enriched in either osteoblasts or CVCs. Finally, we compared expression patterns of CVC-specific genes with patient expression data from carotid plaque versus intact adjacent tissue, and identified five rosiglitazone targets to be differentially regulated in CVCs and carotid plaque but not osteoblasts when compared to their non-mineralizing counterparts. These targets, i.e., PDK4, SDC4, SPRY4, TCF4 and DACT1, may specifically control extracellular matrix mineralization in vascular cells, and hence provide target candidates for further investigations to improve vascular health.
Cognitive Performance during the Development of Diabetes in the Zucker Diabetic Fatty Rat
Authors: Spoelder Marcia , Bright Yami , Morrison Martine C. , van Kempen Veerle , de Groodt Lilian , Begalli Malvina , Schuijt Nikita , Kruiger Eva , Bulthuis Ronald , Gross Gabriele , Kleemann Robert , van Diepen Janna A. , Homberg Judith R.
Published: October 2023

Increased insulin levels may support the development of neural circuits involved in cognition, while chronic mild inflammation may also result in cognitive impairment. This study aimed to gain more insight into whether cognition is already impacted during adolescence in a genetic rat model for obesity and type 2 diabetes. Visual discrimination learning throughout adolescence and the level of motivation during early adulthood were investigated in Zucker Diabetic Fatty (ZDF) obese and ZDF lean rats using operant touchscreens. Blood glucose, insulin, and lipids were longitudinally analyzed. Histological analyses were performed in the liver, white adipose tissues, and the prefrontal cortex. Prior to the experiments with the genetic ZDF research model, all experimental assays were performed in two groups of outbred Long Evans rats to investigate the effect of different feeding circumstances. Adolescent ZDF obese rats outperformed ZDF lean rats on visual discrimination performance. During the longitudinal cognitive testing period, insulin levels sharply increased over weeks in ZDF obese rats and were significantly enhanced from 6 weeks of age onwards. Early signs of liver steatosis and enlarged adipocytes in white adipose tissue were observed in early adult ZDF obese rats. Histological analyses in early adulthood showed no group differences in the number of prefrontal cortex neurons and microglia, nor PSD95 and SIRT1 mRNA expression levels. Together, our data show that adolescent ZDF obese rats even display enhanced cognition despite their early diabetic profile.
IL-20 Cytokines Are Involved in the Repair of Airway Epithelial Barrier: Implication in Exposure to Cigarette Smoke and in COPD Pathology
Authors: Barada Olivia , Salomé-Desnoulez Sophie , Madouri Fahima , Deslée Gaëtan , Coraux Christelle , Gosset Philippe , Pichavant Muriel
Published: October 2023

Background: Dysregulated inflammation as seen in chronic obstructive pulmonary disease (COPD) is associated with impaired wound healing. IL-20 cytokines are known to be involved in wound healing processes. The purpose of this study was to use ex vivo and in vitro approaches mimicking COPD to evaluate the potential modulatory role of interleukin-20 (IL-20) on the inflammatory and healing responses to epithelial wounding. Methods: The expression of IL-20 cytokines and their receptors was investigated in lung-derived samples collected from non-COPD and COPD patients, from mice chronically exposed to cigarette smoke and from airway epithelial cells from humans and mice exposed in vitro to cigarette smoke. To investigate the role of IL-20 cytokines in wound healing, experiments were performed using a blocking anti-IL-20Rb antibody. Results: Of interest, IL-20 cytokines and their receptors were expressed in bronchial mucosa, especially on airway epithelial cells. Their expression correlated with the disease severity. Blocking these cytokines in a COPD context improved the repair processes after a lesion induced by scratching the epithelial layer. Conclusions: Collectively, this study highlights the implication of IL-20 cytokines in the repair of the airway epithelium and in the pathology of COPD. IL-20 subfamily cytokines might provide therapeutic benefit for patients with COPD to improve epithelial healing.
Restraining Quiescence Release-Related Ageing in Plant Cells: A Case Study in Carrot
Authors: Schulz Katie , Machaj Gabriela , Knox Paul , Hancock Robert D. , Verrall Susan R. , Korpinen Risto , Saranpää Pekka , Kärkönen Anna , Karpinska Barbara , Foyer Christine H.
Published: October 2023

The blackening of cut carrots causes substantial economic losses to the food industry. Blackening was not observed in carrots that had been stored underground for less than a year, but the susceptibility to blackening increased with the age of the carrots that were stored underground for longer periods. Samples of black, border, and orange tissues from processed carrot batons and slices, prepared under industry standard conditions, were analyzed to identify the molecular and metabolic mechanisms underpinning processing-induced blackening. The black tissues showed substantial molecular and metabolic rewiring and large changes in the cell wall structure, with a decreased abundance of xyloglucan, pectins (homogalacturonan, rhamnogalacturonan-I, galactan and arabinan), and higher levels of lignin and other phenolic compounds when compared to orange tissues. Metabolite profiling analysis showed that there was a major shift from primary to secondary metabolism in the black tissues, which were depleted in sugars, amino acids, and tricarboxylic acid (TCA) cycle intermediates but were rich in phenolic compounds. These findings suggest that processing triggers a release from quiescence. Transcripts encoding proteins associated with secondary metabolism were less abundant in the black tissues, but there were no increases in transcripts associated with oxidative stress responses, programmed cell death, or senescence. We conclude that restraining quiescence release alters cell wall metabolism and composition, particularly regarding pectin composition, in a manner that increases susceptibility to blackening upon processing.
Development of New Genome Editing Tools for the Treatment of Hyperlipidemia
Authors: Preta Giulio
Published: October 2023

Hyperlipidemia is a medical condition characterized by high levels of lipids in the blood. It is often associated with an increased risk of cardiovascular diseases such as heart attacks and strokes. Traditional treatment approaches for hyperlipidemia involve lifestyle modifications, dietary changes, and the use of medications like statins. Recent advancements in genome editing technologies, including CRISPR-Cas9, have opened up new possibilities for the treatment of this condition. This review provides a general overview of the main target genes involved in lipid metabolism and highlights the progress made during recent years towards the development of new treatments for dyslipidemia.
Updating Ortho- and Metachromatic Acridine Orange Fluorescence in Cytochemical Chromosome Staining: A Proposal for Understanding Its Differential Fluorescence on Double- and Single-Stranded Nucleic Acids Substrates Based on Intercalation
Authors: Stockert Juan C. , Blázquez-Castro Alfonso
Published: October 2023

Many fluorophores display interesting features that make them useful biological labels and chemosensors, in particular in Cell Biology. Changes in the absorption-emission spectra (ortho- and metachromasia) are accounted among them. Acridine orange (AO) is one such fluorochromes that shows a prototypical orthochromatic vs. metachromatic behavior depending on its concentration and binding mode to different cellular substrates. Here, we revisit the differential AO fluorescence that occurs in selected biological examples, which allows for the identification of single-stranded or double-stranded nucleic acids. Although known for long, the ultimate reason for this phenomenon has not been properly advanced. We provide a potential molecular mechanism that adequately accounts for the different aspects of the phenomenon. This theoretical mechanism implies a difference in the degree of overlap of excited state orbitals whenever AO molecules are interacting with a single-stranded or a double-stranded nucleic acid. In the first case, massive π-electron overlapping between bases and intercalated AO leads to a metachromatic red emission. On the contrary, no excited-state orbital overlapping in AO-intercalated DNA duplexes is possible due to excessive separation between AO molecules and compliancy to the nearest neighbor exclusion principle, which manifests as orthochromatic green fluorescence.
Understanding School Anxiety in Italian Adolescence through an Artificial Neural Network: Influence of Social Skills and Coping Strategies
Authors: Morales-Rodríguez Francisco Manuel , Martínez-Ramón Juan Pedro , Narváez Peláez Manuel Alejandro , Corvasce Catalda
Published: October 2023

School anxiety depends on multiple factors that occur directly or indirectly in the teaching–learning process, such as going to the blackboard in class or reporting low grades at home. Other factors that influence school climate are social skills and coping strategies. That said, the aim of this research was to analyze the sources of school anxiety, coping strategies, and social skills in Italian secondary school students through an artificial neural network. For this purpose, a quantitative and ex post facto design was used in which the Inventory of School Anxiety (IAES), the Coping Scale for Children (EAN), and the Questionnaire for the Evaluation of Social Skills student version (EHS-A) were administered. The results showed that cognitive avoidance and behavioral avoidance coping strategies, together with the lack of social skills in students, are the variables that contributed the most to school anxiety scores in the artificial neural network. The conclusions revolve around the need to develop primary prevention programs.
Identification of Metabolomic Signatures for Ischemic Hypoxic Encephalopathy Using a Neonatal Rat Model
Authors: Shevtsova Yulia , Eldarov Chupalav , Starodubtseva Natalia , Goryunov Kirill , Chagovets Vitaliy , Ionov Oleg , Plotnikov Egor , Silachev Denis
Published: October 2023

A study was performed to determine early metabolomic markers of ischemic hypoxic encephalopathy (HIE) using a Rice–Vannucci model for newborn rats. Dried blood spots from 7-day-old male and female rat pups, including 10 HIE-affected animals and 16 control animals, were analyzed by liquid chromatography coupled with mass spectrometry (HPLC-MS) in positive and negative ion recording modes. Multivariate statistical analysis revealed two distinct clusters of metabolites in both HPLC-MS modes. Subsequent univariate statistical analysis identified 120 positive and 54 negative molecular ions that exhibited statistically significant change in concentration, with more than a 1.5-fold difference after HIE. In the HIE group, the concentrations of steroid hormones, saturated mono- and triglycerides, and phosphatidylcholines (PCs) were significantly decreased in positive mode. On the contrary, the concentration of unsaturated PCs was increased in the HIE group. Among negatively charged molecular ions, the greatest variations were found in the categories of phosphatidylcholines, phosphatidylinositols, and triglycerides. The major metabolic pathways associated with changed metabolites were analyzed for both modes. Metabolic pathways such as steroid biosynthesis and metabolism fatty acids were most affected. These results underscored the central role of glycerophospholipid metabolism in triggering systemic responses in HIE. Therefore, lipid biomarkers’ evaluation by targeted HPLC-MS research could be a promising approach for the early diagnosis of HIE.
Cardiac Toxicities in Oncology: Elucidating the Dark Box in the Era of Precision Medicine
Authors: Samuel Younan , Babu Aswin , Karagkouni Foteini , Ismail Ayden , Choi Sunyoung , Boussios Stergios
Published: October 2023

Despite current advancements in chemotherapy, immunotherapy and targeted treatments, the potential for major adverse cardiovascular events, regardless of previous cardiac history, persists. Scoring systems, such as the Heart Failure Association-International Cardio-Oncology Society (HFA-ICOS) risk assessment tool, can be utilized to evaluate several factors including prior cardiac history, risk factors and cardiac biomarkers to categorize patients into low, moderate, high, and very high-risk groups. Common cardiotoxicity complications include new or worsening left ventricular ejection fraction (LVEF), QT interval prolongation, myocardial ischaemia, hypertension, thromboembolic disease, cardiac device malfunction and valve disease. Baseline electrocardiogram (ECG) and transthoracic echocardiogram (TTE) are routinely performed for all patients commenced on cardiotoxic treatment, while other imaging modalities and biochemical markers have proven useful for monitoring. Management mainly includes early risk stratification and prompt identification of cardiovascular complications, with patient-specific surveillance throughout treatment. A multidisciplinary approach is crucial in determining the relationship between potential treatment benefits and cardiotoxicity, and whether the continuation of treatment is appropriate on a case-by-case basis. Early risk stratification, optimizing the patient’s cardiovascular status prior to treatment, and prompt identification of suspected cardiotoxicity are key in significantly reducing risk. This article provides a comprehensive review of the various types of treatment-related cardiotoxicity, offering guidance on identifying high-risk patients, recognizing early signs of cardiotoxicity, and outlining appropriate treatment approaches and follow-up care for such cases.
Association of OXTR, AVPR1a, LNPEP, and CD38 Genes’ Expression with the Clinical Presentation of Autism Spectrum Disorder
Authors: Wilczyński Krzysztof Maria , Auguściak-Duma Aleksandra , Stasik Aleksandra , Cichoń Lena , Kawalec Alicja , Janas-Kozik Małgorzata
Published: October 2023

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that affects social interactions, communication, and behavior. Although the predominant genetic predisposition to ASD seems beyond doubt, its exact nature remains unclear. In the context of social cognition disorders and the basis of ASD, the oxytocinergic and vasopresynergic systems arouse great interest among researchers. The aim of the present study was to analyze gene expression levels for oxytocin and vasopressin receptors, as well as CD38 protein and oxytocinase, in the context of the clinical picture of autism spectrum disorders. The study included 90 people, of whom 63 were diagnosed with ASD based on anamnesis, mental status testing, and the ADOS-2 protocol. The results obtained in the presented study indicate that the balance between the levels of expression of the CD38 gene and the oxytocinase gene plays a key role in the risk and clinical presentation of ASD. In a hypothetical scenario, an imbalance in the expression of CD38 and LNPEP could potentially lead to alterations in the concentrations of oxytocin and vasopressin. At the same time, the most frequently studied genes—AVPR1a and OXTR—seem to be at best of marginal importance for the risk of ASD.
Extremophilic Solutions: The Role of Deinoxanthin in Counteracting UV-Induced Skin Harm
Authors: Kuzucu Mehmet
Published: October 2023

This research delved into the protective capacities of deinoxanthin, a carotenoid present in Deinococcus radiodurans, against UVA- and UVB-mediated skin damage using human fibroblast foreskin cells (HFF-1). Using the MTT assay, HFF-1 cells treated with 10 µM DNX displayed 20% and 31.7% higher viability than the positive (Vitamin C-treated) and negative (DNX-untreated) control groups, respectively, upon 100 mJ/cm2 UVB exposure. At 24 J/cm2 UVA, 20 µM DNX-treated cells showed 80.6% viability, exceeding the positive and negative control groups by 28.6% and 33.6%, respectively. Flow cytometry analysis revealed that cells treated with DNX and exposed to 24 J/cm2 UVA exhibited a 69.32% reduction in apoptotic processes compared to untreated cells. Similarly, when exposed to 100 mJ/cm2 UVB, DNX-treated cells demonstrated a 72.35% decrease in apoptotic processes relative to their untreated counterparts. DNX also displayed dose-dependent inhibition on tyrosinase activity. The study emphasized DNX’s antioxidative capacity, evident in its modulation of superoxide dismutase activity and measurements of Malondialdehyde and intracellular reactive oxygen species levels. DNX-treated cells exhibited higher hydroxyproline levels, suggesting healthier collagen production. Additionally, the wound-healing assay method confirmed an accelerated healing rate in DNX-treated cells. Conclusively, DNX offers significant protection against UV-induced skin damage, emphasizing its potential for skincare and therapeutics.
Relationship between Telework Jetlag and Perceived Psychological Distress among Japanese Hybrid Workers
Authors: Matsumoto Yuuki , Hino Ayako , Kumadaki Kunitaka , Itani Osamu , Otsuka Yuichiro , Kaneita Yoshitaka
Published: October 2023

Social jetlag is associated with physical and mental health problems. With the increased popularity of telework, we investigated a specific form of social jetlag that we termed “telework jetlag”. This study aimed to clarify the relationship between telework jetlag—the difference in sleep and wake-up times between in-office and telework days—and mental health problems among Japanese hybrid workers. A cross-sectional study was conducted with 1789 participants from October to December 2021 using an online-based questionnaire. Telework jetlag, defined as the difference in the midsleep point between in-office and telework days, was investigated using two groups according to telework jetlag—those lagging <1 h versus ≥1 h. We used the six-item Kessler Scale as a nonspecific psychological distress scale for the outcome. Telework jetlag was significantly associated with psychological distress, and the ≥1 h group had a higher risk (odds ratio: 1.80) of developing high psychological distress (HPD) than the <1 h group in the multivariate analysis. Since most teleworkers are forced to have a hybrid work style that mixes going to work and teleworking, telework jetlag must be addressed to maintain the health of teleworkers.
Effect of Carrier Gas on the Gas Sensing Performance of Co1−2xNixMnxFe2−yCeyO4 Double-Substitution Spinel in Flammable Gases and Volatile Organic Compounds
Authors: Ogundipe Sunday A. , Ndlangamandla Ceboliyazakha L. , Diale Mmantsae M. , Jozela Mudalo , Swart Hendrik C. , Motaung David E. , Nkosi Steven S.
Published: October 2023

The presence of high concentrations of flammable gases and volatile organic compounds in the atmosphere has been widely reported to be detrimental to human survival. A lot of research effort has been put toward finding an efficient means of quick detection of these gases below their ‘immediately dangerous to life or health’ concentrations. Detecting these gases in an oxygen-deficient environment is a crucial task to consider and has been overlooked. In this research, double-substitution spinel with the chemical formula Co1−2xNixMnxFe2−yCeyO4, where 0 ≤ x = y ≤ 0.3, was prepared via the glycol-thermal technique. The final products, following appropriate substitution, were CoFe2O4 (dried naturally), CoFe2O4 (dried with infrared lamp), Co0.8Ni0.1Mn0.1Fe1.9Ce0.1O4, Co0.6Ni0.2Mn0.2Fe1.8Ce0.2O4 and Co0.4Ni0.3Mn0.3Fe1.7Ce0.3O4 spinel ferrites. The X-ray diffractometry (XRD), high-resolution transmission electron micrographs (HRTEM) and X-ray photoelectron spectroscopy (XPS) of the samples confirmed the formation of the spinel. The gas sensing performance of these samples was tested at the operating temperature of 225 °C toward liquefied petroleum gas (LPG), ammonia, ethanol and propanol. The Co0.8Ni0.1Mn0.1Fe1.9Ce0.1O4-based sensor was selective to LPG, with a high response of 116.43 toward 6000 ppm of LPG when helium was used as the carrier gas, 3.35 when dry air was the carrier gas, 4.4 when nitrogen was the carrier gas, but it was not sensitive when argon was used as the carrier gas.
A Study on the Influence of the Electroplating Process on the Corrosion Resistance of Zinc-Based Alloy Coatings
Authors: Cao Fan , Wang Jianpeng , Lian Yuli , Wang Yuanhao , Wang Xue , Wang Xiaomin , Song Aiqing , Shi Lei
Published: October 2023

A comprehensive analysis was conducted to examine the crystal phase composition, surface and cross-section morphology, elemental composition, thickness, and corrosion resistance of coatings. X-ray diffraction (XRD) was employed to investigate the texture and crystal phase of the materials while scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS) were utilized to assess the surface and cross-section structure. Additionally, electrochemical techniques were employed to evaluate the corrosion performance. Compared to DC electroplating, the corrosion potential of pulsed galvanized ferroalloy alloy coating increased from −1031 mV to −1008 mV, and the corrosion current density decreased from 3.122 × 10−5 A∙cm−2 to 0.321 × 10−5 A∙cm−2. Moreover, the corrosion rate value of the coating obtained by the pulse rectifier (0.386 × 10−5 g m−2 h−1) was lower than that obtained by the DC power supply (3.75 × 10−5 g m−2 h−1). Additionally, pulsed electrodeposition reduced the iron content of the coating by 0.7%, thereby enhancing its corrosion resistance and flatness. The impedance parameters of the zinc–iron alloy coating acquired through the 30% duty cycle monopulser process exhibit superior performance compared to DC electroplating. Evidently, the monopulse coating’s structure enhances crystal packing density, augments coating thickness, improves adhesion to the substrate interface, and optimizes grain distribution uniformity. These factors are crucial determinants of the corrosion behavior exhibited by Ze–Fe coating.