bluuebunny/crossref_metadata_2025 huggingface dataset:
Using cell-free RNA in monitoring immune system and the demonstration of significant systemic deficiency in lymphoid and myeloid biomarkers in patients with cancer.
Authors: Albitar Maher , Zhang Hong , Charifa Ahmad , Ip Andrew , Agersborg Sally , Mohtashamian Arash , Siegel David Samuel DiCapua , Waintraub Stanley E. , Gutierrez Martin , Pecora Andrew L , Goy Andre
Published: June 2024

3048

Background: Immune system plays a major role in the clinical course of cancer. Evaluating the local interaction between tumor cells and the immune cells (microenvironment) at the cancer site provides important information. However, currently little is known about the immune system as a whole in patients with cancer. Since cell-free circulating RNA (cfRNA) may reflect the entire body, we hypothesized that cfRNA might provide important information on the health and the status of the immune system. To simplify our approach, we evaluated only cellular biomarkers characteristic for lymphoid and myeloid cells using only the expression of 55 genes typically used in flow cytometry evaluation of hematologic cells. We compared findings between patients with cancer, patients with CHIP (clonal hematopoiesis of indeterminate potential), and normal individuals. Methods: cfRNA was extracted from plasma samples of 681 patients with various types of solid tumors, 113 patients with CHIP, and 34 normal individuals. cfRNA was sequenced via a hybrid capture-based panel targeting 55 genes reflecting immune cells including T-cells, B-cells, histiocytes, monocytes, and myeloid cells. The RNA was quantified using TPM (transcript per million). Results: There was significant difference (P<0.0001) between normal individuals and patients with cancers in the levels of circulating biomarkers specific for immune cells. Surprisingly, expression of B-cell, T-cell, monocytic/histiocytic genes were significantly lower in patients with solid tumors when compared to normal individuals. This included CD19, CD20, CD2, CD22, CD3D, CD3E, CD3G, CD4, CD52, CD7, CD79A, CD79B, CD8A, CD8B,CD33, FCER2(CD23), IL2RA(CD25), ITGAM(CD11B), and ITGAX(CD11C). In contrast, there was no significant difference between CHIP and normal for B- or T-cell markers. After adjusting for multiple testing, no deficiency in immune stimulatory markers was present in patients with CHIP. Patients with CHIP showed significantly (P<0.001) lower levels of CD38, CD58, CD16, CD15, CD25, and CD123 mRNA as compared with normal. Furthermore, using 35 immune cell biomarkers in a machine learning algorithm using 2/3 of samples for training and 1/3 for testing predicted the presence of cancer vs no cancer (AUC =0.820), and CHIP from cancer (AUC =0.0830) and CHIP vs normal (AUC =0.871). Conclusions: Immune related biomarkers using cfRNA provide important information on the immune system that can be used to monitor patients and to predict the presence of cancer or CHIP. The demonstration that patients with cancer have deficiency in overall systemic immune elements suggests that further studies are needed in monitoring the immune system and exploring means to boost systemic immunity to prevent the development of overt cancers.
Personalized circulating tumor DNA for minimal residual disease and dynamic assessment in patients undergoing neoadjuvant chemotherapy for breast cancer: Preliminary analysis from MSK-LINC.
Authors: Kim Hong-Kyu , An Julia Ah-Reum , Smith Christopher Gareth , KIM Jisun , Cabel Luc , Moiso Enrico , Ferraro Emanuela , Safonov Anton , Nelson Konner , Szuhany Kathleen , Drago Joshua Z. , Norton Larry , Xu Amy , Scher Howard I. , Chandarlapaty Sarat , Khan Atif J. , Li Bob T. , Robson Mark E. , Plitas George , Razavi Pedram
Published: June 2024

3049

Background: Identification of minimal residual disease (MRD) with circulating tumor DNA (ctDNA) in pts with early-stage breast cancer holds promise to identify risk of relapse. MSK-LINC is prospective ctDNA plasma analysis of breast cancer pts. This pilot study evaluated the utility of serial ctDNA assessment as a biomarker for monitoring MRD and recurrence prediction in clinical stage II-III breast cancer pts undergoing neoadjuvant chemotherapy (NAC). Methods: 30 pts who underwent NAC across all subtypes were identified from MSK-LINC. The ctDNA analysis was performed at baseline, on-NAC, post-NAC/pre-surgery, within 8 weeks post-surgery, and during follow-up. Personalized ctDNA RaDaR assays were designed using whole exome sequencing data of paired primary tumor and germline samples from each pt. ctDNA levels were quantified as an estimated variant allele fraction (eVAF). Results: ctDNA panels were successfully designed for 29/30 pts (16 Stage II, 13 Stage III), including 6 HR+/HER2-, 12 HER2+, and 11 TNBC, with a median follow up of 4.2 years. The bespoke ctDNA assays targeted a median of 48 variants (21-51), with a median of 43 variants (11-48) passing quality control. A total of 175 plasma samples were analyzed, including 24 baseline and 24 post-surgery. A 100% ctDNA detection rate was observed at baseline in the 24 pts for whom a baseline sample was available (median eVAF 0.33%, range 0.0083% - 8.91%). Pathologic complete response (pCR) was achieved in 11 pts who remained disease free; and of the 18 pts without a pCR, 5 recurred. All patients with a pCR were ctDNA negative post treatment. In 3/5 patients who recurred, MRD detection was achieved, including one patient with persistent ctDNA positivity throughout all timepoints. For the other two pts, ctDNA was first detected in follow-up plasma collected at 4.4 and 9.8 months prior to clinical recurrence. Conclusions: This study demonstrates the potential of ctDNA as a dynamic biomarker for monitoring disease burden in pts with high-risk early-stage breast cancer, highlighting its remarkable sensitivity at baseline and its capability for MRD detection preceding clinical recurrence. These findings suggest the need for further research to fully understand the relationship between ctDNA dynamics during and after NACT with prediction of breast cancer outcomes. ctDNA detection rates in plasma samples across collection timepoints. [Table: see text]
Enhancing cancer detection through AI-driven high content analysis of circulating tumor cells.
Authors: Apurwa Sachin , Shaikh Muqeet , Devhad Sagar , Patel Shoeb , Chougule Rohit , Shejwalkar Pradyumna , Adhav Archana , Dalvi Apurva , Akolkar Dadasaheb , Patil Darshana , Datar Rajan , Vaid Ashok K
Published: June 2024

3054

Background: The advancements in automated High Content Analysis (HCA) for Circulating Tumor Cells (CTCs) detection necessitate the integration of high-throughput screening (HTS) and Artificial Intelligence (AI) to improve cancer diagnosis efficiency and accuracy. Traditional approaches to cancer detection have faced limitations in speed, cost, and analysis depth, driving the need for innovative solutions in assay development and execution. Methods: We obtained peripheral blood from 150 asymptomatic individuals and 63 newly diagnosed cases of solid organ cancers including Lung, Breast, Head and Neck, Colorectal, Pancreas, Esophagus, Gynecologic cancers. We used differential apoptosis based negative enrichment technique and HCS fluorescent imaging for identification of CTCs and CTC like immune cells from the relevant blood samples. We devised AutoML algorithms which were trained on a cohort of 4,135 cropped region of interest (ROI) images of true CTCs and CTC-mimicking immune cells. These images were annotated with the coordinates of the top-left and bottom-right corners of rectangles to specify ROIs. This method employs a combination of automated sample processing, integration with the Laboratory Information Management System (LIMS) integration, digital filtration, and decision matrix algorithms for sample classification and smooth data flow. The image quality criteria were established prior to dataset analysis. The algorithms underwent training, testing, and validation based on expert recommendations, with dataset splitting of 80% for training, 10% for testing, and 10% for validation phases. Results: The automated deep learning model achieved remarkable performance metrics, presenting an accuracy of 96.66% (95% CI, 96.07%-97.19%), a specificity of 95.34% (95% CI, 94.37%-96.18%), and a sensitivity of 98.14% (95% CI, 97.44%-98.69%) in detecting true CTCs. Additional analysis included the area under the curve and confusion matrix evaluations, indicating the model's robustness in distinguishing between true positive and true negative specimens. This efficiency and precision in data handling, processing, and analysis demonstrate significant advancements in HCA screening, offering enhanced assay development, execution flexibility, and the facilitation of detailed cell-by-cell analysis for cancer detection from a large set of Peripheral Blood Mononuclear Cells (PBMCs) from samples obtained for screening or diagnosis. Conclusions: This study successfully evaluated a deep learning model for the detection of circulating tumor cells (CTCs) in peripheral blood mononuclear cells (PBMCs) using image data from HTS platform. The model achieved superior performance, demonstrating its potential for cancer detection from blood samples.
Discovery of long non-coding RNA biomarkers for prognosis in pediatric acute lymphoblastic leukemia.
Authors: Hsieh Tien-Chan , Li Zixiu , Zhou Peng , Zhou Chan
Published: June 2024

3055

Background: Acute lymphoblastic leukemia (ALL) ranks among the most prevalent pediatric cancers. Molecular testing, including cytogenetics, has been widely used for prognosticating pediatric ALL. However, cytogenetic testing in pediatric ALL is incapable of detecting submicroscopic genetic changes and suffers from variable sensitivity, which may lead to heterogeneous outcomes within cytogenetic subgroups. In addition to conventional prognostic biomarkers, long non-coding RNAs (lncRNAs) are expressed in both a disease- and tissue-specific manner, emerging as promising biomarkers. However, well-established lncRNA prognostic biomarkers for pediatric ALL have yet to be identified. Therefore, in this study, we discovered three singular lncRNA prognostic biomarkers and a prognostic panel composed of multi-lncRNAs for pediatric ALL using our newly developed BAMBI method. Methods: This study utilized RNA-seq data from 561 distinct individuals, comprising 647 blood or bone marrow biospecimens obtained from pediatric patients with ALL from the dbGaP TARGET dataset. Among these individuals with RNA-seq and survival data, 25.8% deceased during follow-up. The average age at enrollment was 8.1 years. Of this cohort, 36.0% were female, and 61.5% were Caucasian white. Initially, our lncRNA identification tool, Flnc (Li Z., et al., Noncoding RNA. 2022), was employed to identify and quantify both novel and known lncRNAs expressed in pediatric ALL. Subsequently, our machine-learning based method, BAMBI, was utilized to discover lncRNAs as new prognostic biomarkers in pediatric ALL. Results: Three lncRNAs (ZBTB47 and NKTR antisense RNA, AC097359.2’s new isoform, and a novel lncRNA near STXBP5) were identified as individual putative biomarkers for prognosis. Each of these three lncRNA biomarkers exhibited predictive power for survival, with accuracy ranging from 68.2% to 72.8% and AUROC scores ranging from 67.7% to 75%. Furthermore, we established three lncRNA biomarker panels composed of these three lncRNAs along with a few additional lncRNAs, which showed improved prediction power with accuracy ranging from 78.3% to 79.6%, and AUROC scores ranging from 82.1% to 85.2%. Conclusions: We discovered both singular lncRNA and panels of multi-lncRNAs as prognostic biomarkers of pediatric ALL patients. These putative lncRNA biomarkers could be further validated through independent cohorts or prospective clinical study designs.
Correlation of ctDNA and radiographic imaging features derived from 18F-FDG PET/CT for patients with metastatic melanoma treated with immunotherapy.
Authors: Dell'Oro Mikaela R. , Lokre Ojaswita , Gray Elin S. , Francis Roslyn J. , Perk Timothy G. , Ebert Martin A. , Millward Michael
Published: June 2024

3057

Background: 18F-FDG PET/CT scans are used to assess tumor response for patients undergoing immunotherapy for metastatic melanoma (MM). Evaluating the relationship between features derived from quantitative medical image analysis and markers in blood samples such as circulating tumor DNA (ctDNA) may present an opportunity to discover imaging and blood biomarkers that can influence future patient care. This study evaluates the correlation of ctDNA and radiographic imaging features derived from FDG PET/CT. Methods: Whole-body FDG PET/CT scans from MM patients between 2014-2020 were retrospectively collected under IRB-approved protocol. Patients received pembrolizumab (n=20), ipilimumab (n=4), nivolumab (n=7), or a combination of ipilimumab and nivolumab (n=19). TRAQinform IQ software (AIQ Solutions) identified and quantified regions of interest suspicious of cancer (lesion-ROI), enabling extraction of imaging features including SUVmax, SUVmean, and SUVtotal in baseline (BL) and follow-up (FU) images and change. Plasma ctDNA concentration (copies/ml) and frequency abundance (FA) were evaluated for the first sample (1) after immunotherapy had started (between baseline and first on-treatment scan), and the next available sample (2). Patients were further grouped by ctDNA mutation for analysis. Correlation between imaging features and ctDNA features was assessed using Spearman coefficient (ρ). Results: The patient cohort included 32 males and 19 females with average age of 62 years (range 23-83). For all 51 patients, moderate correlation was observed in SUVmax,BL with ctDNA copies/ml1 (ρ = 0.48, p<< 0.001) and ctDNA FA1 (ρ = 0.49, p << 0.001) and in SUVtotal,BL with ctDNA FA1 (ρ= 0.41, p < 0.001). In BRAF mutation patients (N=32), moderate correlations existed between SUVmax,BL with ctDNA copies/ml1 (ρ = 0.49, p = 0.0041 and ctDNA FA1 (ρ = 0.05, p = 0.0035), and SUVtotal,BL with ctDNA copies/ml2 (ρ = 0.42, p = 0.017), ctDNA FA1 (ρ = 0.40, p = 0.023), and ctDNA FA2 (ρ = 0.43, p = 0.012). All the other combinations displayed weak correlations (ρ < 0.39, p > 0.05). Conclusions: This study shows that in patients with MM receiving immunotherapy, quantitative features from blood biomarkers such as ctDNA correlate with FDG PET/CT imaging features. Combining blood biomarkers with imaging features that are spatially localizable may strengthen prognostication in this patient group. Further analysis is being performed with more types of ctDNA mutations.
Nature and distribution of methyl thioadenosine phosphorylase (MTAP) genomic loss in human tumors.
Authors: Necchi Andrea , Cigliola Antonio , Tateo Valentina , Mercinelli Chiara , Ross Jeffrey S. , Pavlick Dean
Published: June 2024

3067

Background: MTAP genomic loss, often but not exclusively a bi-allelic homozygous deletion, has recently emerged as important biomarker guiding a novel synthetic lethality mechanism for drugs in the class of PRMT5 and MAT2A inhibitors. In the current study, we assessed the nature and distribution of MTAP complete and partial loss in a variety of tumor samples. Methods: A total of 291,391 tissue samples underwent comprehensive genomic profiling (CGP) using a hybrid-capture method to evaluate all classes of genomic alterations (GA), and determine the microsatellite instability (MSI) status, tumor mutational burden (TMB), homologous recombination deficiency (HRD) score and genomic ancestry. The distribution of both complete and partial loss of MTAP was also determined. Results: MTAP GA were found in 8.6% of total with 9.3% genomic loss and 0.1% each short variant mutations and rearrangements. Important (not rare) tumor types with the most frequent MTAP loss included: 42.6% of glioblastoma (GBM), 13.4% of non-small cell lung cancer (NSCLC), 22.3% of pancreatic ductal and 24.9% of bladder urothelial carcinomas. The most frequently co-altered GA included CDKN2A (99.7%), CDKN2B (95.1%), TP53 (55.4%), KRAS (30.1%), TERT(20.5%) and PIK3CA (12%). In tumor types with frequent known targetable driver GA including short variant mutations in EGFR, ERBB2, BRAF, FGFR2-3and MET and fusions involving ALK, RET, ROS1 and NTRK1-3, MTAP loss was not associated with decreased frequencies of GA in these genes. The frequencies of MSI-high status was 0.3% and of TMB≥10 mut/Mb was 17%. In total, 63.7% of the MTAP loss cases involved deletion of all 8 MTAP exons (complete loss) with partial loss accounting for 36.3% of cases. All partial loss cases involved loss of multiple exons (35.8%) except for loss of only exon 8 (0.5%). There was no impact of MTAP loss status on genomic ancestry, cosmic trinucleotide signature and HRD score. The multiple exon loss frequencies included exons 2-8 loss in 24.7%, exons 5-8 loss in 4.1%, exons 6-8 loss in 3.3%, exons 3-8 loss in 1.6%, exons 7-8 in 1.1%, exon 4-8, 1-5, 2-7,2-5, 1-4, 2-6, 3-7 and 5-7 all at less than 1% frequencies. Conclusions: MTAPloss is a frequent GA of emerging clinical importance as the trials using PRMT5 and MTA-2 inhibitors progress. MTAPloss is frequent in common cancers of the brain, lung, pancreas and bladder and not associated with diminishment of other targetable driver mutations. Although one-third of MTAP loss is a partial loss, the partial loss cases involve near total (exons 2-8) loss and may well also be indicative of PRMT5/MAT2A inhibitor benefit. This study strengthens the opportunity to consider a tumor-agnostic approach to targeted therapies. [Table: see text]
Therapeutic implications of phosphoproteomics in molecular cancer diagnostics.
Authors: Schneider Annika , Woortman Julia , Jensen Cecilia Bang , Sakhteman Amirhossein , Teleanu Maria-Veronica , Horak Peter , Kreutzfeldt Simon , Hutter Barbara , Huellein Jennifer , Resch Moritz , Stange Christoph , Lee Chien-Yun , Witt Olaf , Jones David T.W. , Hübschmann Daniel , Pfister Stefan M. , Weichert Wilko , The Matthew , Froehling Stefan , Kuster Bernhard
Published: June 2024

3068

Background: Precision oncology approaches employing genomics-guided targeted therapies for individual patients have provided significant survival benefits in several cancer types. However, varying response rates in solid malignancies, many patients without actionable genomic lesions, and increasing evidence that non-genomic mechanisms may play an important role in tumors indicate that genomics alone is often insufficient to inform and guide the clinical care of patients. Since most targeted anti-cancer drugs inhibit the activity of protein kinases, measuring the tumor phosphoproteome as a direct readout of oncogenic pathway activity is poised to enhance molecular stratification. Methods: We established a clinical (phospho)proteomic workflow for integration into the molecular tumor board (MTB) workflow of the Germany-wide INFORM (for children with relapsed cancers) and MASTER (for young adults with refractory cancers and patients with rare tumors) registry studies and profiled > 1000 tumor tissue specimen from patients enrolled in the DKFZ/NCT/DKTK MASTER study or the INFORM registry trial. To assess the aberrant activity of druggable signaling pathways, we developed a new tumor pathway activity (TUPAC) scoring methodology using expression data of > 8,000 proteins and > 20,000 phospho-sites per patient in a heterogeneous pan-cancer cohort. TUPAC scores integrate protein expression and phosphopeptide abundance data at several levels to detect aberrant signaling pathway activities of several interdependent oncogenic signaling pathways within one tumor specimen. Results: We show for the first time that comprehensive (phospho)proteome profiling is feasible and informative in a real-world prospective precision oncology setting. Discussion of (phospho)proteomic data of > 500 prospective patients in weekly MTB meetings revealed that adding a (phospho)proteomic layer can supply critical information for personalized therapies that is not discernible from genomic and transcriptomic data. In an independent value evaluation (329 target recommendations in 104 patients), the phosphoproteome layer was decisive in 22% of all recommended targets. Based on anecdotal cases with available clinical follow-up, we provide evidence that (phospho)proteome profiling carries important diagnostic value by detecting actionable tumor-driving kinase signaling in patients without actionable genomic lesions or by functionalizing genomic variants of unknown significance. Conclusions: Measuring the tumor phosphoproteome as a direct readout of oncogenic pathway activity is feasible and adds complementary, therapy-relevant information in a real-world prospective precision oncology setting.
CDK7 as a biomarker to predict response to etoposide and carboplatin treatment in limited-stage small cell lung cancer with surgical resection.
Authors: Tong Shanshi , Lin Chengbin , Shen Weiyu
Published: June 2024

e20104

Background: The etoposide and carboplatin (EC) treatment has achieved great success in the adjuvant therapy of small cell lung cancer (SCLC), but its response rate is still low. However, there are currently no good biological indicators to suggest EC treatment sensitivity in limited-stage small cell lung cancer (LS-SCLC) patient with surgical resection. We aimed to explore reliable biomarkers for EC treatment during adjuvant therapy. Methods: We chose LS-SCLC patients undergoing adjuvant etoposide and carboplatin (4 cycles) after surgical resection in Ningbo Medical Center Lihuili Hospital from Jan, 2016 to Dec, 2023. Assessments of status including complete remission (CR), partial remission (PR), disease stable (SD) and progressive disease (PD) were according to the efficacy evaluation criteria of solid tumor (RECIST) version 1.1. We collected the clinical characteristics and overall survival (OS) of LS-SCLC patients for analysis. The formaldehyde-fixed, paraffin-embedded samples were collected to conduct immunohistochemistry (IHC) of CDK7 (CST, 2916, 1:1000). The H-score was calculated by IHC Profiler. All statistical analyses were evaluated using Graphpad and Excel. P value < 0.05 were considered statistically significant. Results: Clinical characteristics were displayed in table. The CDK7 expression was significantly correlated with the responsivity. Patients with higher CDK7 expression levels had lower responsivity to EC therapy, while there is no correlation between other clinical indicators (age, gender, smoke, SCLC type and ki-67 index) and EC therapy responsivity. Moreover, the expression of CDK7 and OS displayed significantly negative correlation (P < 0.05). Patients were divided into two groups depends on CDK7 expression. The Kaplan-Meier curves shows that OS was significantly different (P<0.01). Conclusions: Our study indicated that CDK7 acted as a promising biomarker for both EC treatment sensitivity and clinic outcome prediction in LS-SCLC patients with surgery. [Table: see text]
Effect of CDC7 inhibition and MYC degradation on neuroendocrine transformation in the lung and prostate cancer.
Authors: Quintanal-Villalonga Alvaro , Kawasaki Kenta , Redin Esther , Rakhade Swanand , Durani Vidushi , Sabet Amin , Karthaus Wouter , Zaidi Samir , Zhan Yingqian A. , Manoj Parvathy , Sridhar Harsha , Zhong Hong , Mello Barbara , Ciampricotti Metamia , Bhanot Umesh , Haffner Michael C. , Socci Nicholas D. , Yu Helena Alexandra , Chan Joseph Minhow , Rudin Charles M.
Published: June 2024

e20105

Background: Neuroendocrine (NE) transformation occurs as a mechanism of resistance to targeted therapy in up to 14% and 30% of EGFR-mutant lung and AR-dependent prostate adenocarcinomas, respectively, leading to poor prognosis. Even if we know the tumor population at high risk of transformation ( TP53/RB1-mutated), no therapies to prevent NE relapse are currently available. Methods: To identify therapeutic vulnerabilities for tumors undergoing NE transformation, we performed an in vitro CRISPR screen in a NE-transformed lung tumor model, followed by functional validation in in vivo prostate and lung models of NE transformation, including pharmacologic as well as genetic (isogenic cell line with overexpression or knock of CDC7) validation. Results: Our screen identified CDC7, involved in DNA replication and DNA damage response, as a potential therapeutic target in this setting. Proteogenomic analyses revealed CDC7 upregulation in lung and prostate clinical samples undergoing NE transformation, detected already in pre-transformation adenocarcinomas. Importantly, TP53/RB1-inactivation induced sensitivity to the CDC7 inhibitor simurosertib, unraveling a therapeutic vulnerability in tumors at high risk of NE transformation. Thus, we tested the combination of simurosertib with targeted therapy in vivo in different lung and prostate patient-derived models of NE transformation. In these, simurosertib was able to suppress NE transformation and dramatically delay tumor relapse. Trajectory analysis on single-cell transcriptomic data for such models revealed a NE transformation transcriptional program occurring already in the untreated tumors before transformation. CDC7 inhibition led to increased proteasomal activity and degradation of MYC, a stemness transcription factor involved in NE transformation. Ectopic overexpression of MYCT58A, a proteasome degradation-resistant MYC isoform, rescued the NE phenotype in these transformation models, suggesting that CDC7 inhibition-induced MYC degradation is the mechanism by which NE transformation is prevented. Conclusions: In sum, CDC7 inhibition may suppress, or at least dramatically delay NE transformation in patients with lung and prostate adenocarcinomas at high risk of transformation, by inducing MYC proteasomal degradation. The clinical availability of CDC7 inhibitors, currently in phase II clinical trials after demonstrating tolerability and preliminary efficacy, will allow rapid translation of these results into the clinics.
Real world outcomes in extensive stage small cell lung cancer (ES-SCLC) treated with consolidative thoracic radiation (cTRT) and chemoimmunotherapy (CIT): A population level study.
Authors: Gibson Amanda Williams , Dean Michelle Liane , Kerba Marc , Navani Vishal
Published: June 2024

e20111

Background: Despite recent survival improvements from the combination of immune checkpoint inhibitors (ICI) with chemotherapy for patients with ES-SCLC, outcomes remain limited for the majority of patients. Addition of cTRT may elicit a synergistic response and contribute to improved disease control and survival, but there is limited data supporting routine use from either the trial or real world contexts. This study aims to investigate the safety and time-to-event outcomes of patients treated with CIT and cTRT. Methods: Demographic, clinical, treatment and outcome details were extracted from the Glans-Look Lung Cancer Research Database, a province-wide real-world outcomes registry of patients treated in routine practice. A population-level cohort of ES-SCLC patients receiving CIT and cTRT between 2019 and 2023 were identified. Results: 30 patients were identified. Median age was 68y. At CIT initiation; 63% had ECOG performance status ≤ 1, 17% had brain metastases; 20% received prophylactic cranial irradiation. CIT was comprised of platinum-etoposide and ICI: durvalumab (67%) or atezolizumab (33%), followed by maintenance ICI (median 5.8 months). cTRT was administered a median 4.8 months after CIT initiation; n=13 (43%) received 30Gy/10, n=2 (7%) received dose escalation to 40-45Gy in 14-20 fractions, and n= 15 (50%) received 20Gy-25Gy over 5-10 fractions. Reasons for discontinuation of CIT were primarily to progressive disease (n=18, 75%); with n=16 patients receiving second line systemic treatment (94% chemotherapy, 6% durvalumab rechallenge), and n=1 receiving additional thoracic stereotactic ablative body radiation. Post-cTRT pneumonitis was recorded in n=3 (10%) of patients, ranging from (CTCAE v5.0 Grade 1-3 severity), requiring hospitalization + treatment break (n=1), ICI termination (n=1), or resolving without intervention (n=1). Time-to-event outcomes are presented in the table. Receiving durvalumab as opposed to atezolizumab did not impact either mPFS (10 vs. 12 months, log rank=0.4; HR: 1.3 [95% CI: 0.8 - 5.9], p=0.12) or OS (17 vs. 13.2 months, log rank p=0.87; HR: 2.2 [95% CI: 0.4 – 4.4], p=0.67). Conclusions: ES-SCLC treatment comprised of both CIT and cTRT appears feasible and effective in among real-world patients. Pneumonitis, a potential complication of combined ICI and thoracic radiation, was infrequently observed in this cohort. Use of cTRT in addition to CIT appears to numerically surpass the ~13-month mOS observed within clinical trials which used first-line CIT without additional cTRT for ES-SCLC. [Table: see text]
Prospective Associations of Maternal Cardiometabolic Health With Children Cardiometabolic Health at Ages 3 to 6 Years
Authors: Jing Guangzhuang , Ye Peiqi , Wei Qian , Zou Jiaojiao , Zhang Yunhui , Shi Huijing
Published: June 2024

Objective

Maternal cardiometabolic health (MCMH) may have critical effects on offspring lifetime cardiometabolic health (CMH), whereas evidence on the relationship between MCMH during pregnancy and children CMH (CCMH) at ages 3∼6 years remains unknown.

Method

The study included 1478 mother-child dyads from the Shanghai Maternal-Child Pairs Cohort study. MCMH was examined at a mean of 27.8 (24-36) weeks’ gestation based on 8 metrics of the “Life Essential 8” framework involving prepregnancy body mass index, total cholesterol, glucose level, blood pressure, physical activity, sleep, diet quality, and nicotine exposure. CCMH was examined at the age of 3 to 6 based on 5 metrics including body mass index, physical activity, sleep health, diet quality, and nicotine exposure. To validate the robustness of the main analysis, 499 children were selected to reevaluate CCMH by 6 metrics (adding blood pressure) for sensitivity analysis.

Results

Among 1478 mother-child dyads, the mean (SD) MCMH during pregnancy and CCMH scores were 67.07 (SD 8.82) and 73.80 (SD 10.75), respectively. After adjusting important confounders, each 10-point increase in (more favorable) MCMH score was significantly associated with a higher CCMH score [β: .85; 95% confidence interval (CI): .22, 1.47]. Subgroup analysis showed similar results in girls but not in boys. For cardiometabolic risk factors in children, the risk of overweight/obesity and hypertension in children decreased with increased MCMH score [overweight/obesity, relative risks (RRs): .98, 95% CI: .96, .99; hypertension, RRs: .66, 95% CI: .47, .92]. Sensitivity analysis showed similar results.

Conclusion

Better MCMH in pregnancy was associated with better CCMH at ages 3∼6 years.
Foraging task specialization in honey bees (Apis mellifera): the contribution of floral rewards to the learning performance of pollen and nectar foragers
Authors: Moreno Emilia , Arenas Andrés
Published: June 2024

Social insects live in communities where cooperative actions heavily rely on the individual cognitive abilities of their members. In the honey bee (Apis mellifera), the specialization in nectar or pollen collection is associated with variations in gustatory sensitivity, affecting both associative and non-associative learning. Gustatory sensitivity fluctuates as a function of changes in motivation for the specific floral resource throughout the foraging cycle, yet differences in learning between nectar and pollen foragers at the onset of food collection remain unexplored. Here, we examined nectar and pollen foragers captured upon arrival at food sources. We subjected them to an olfactory proboscis extension reflex (PER) conditioning using a 10% sucrose solution paired (S10%+P) or unpaired (S10%) with pollen as a co-reinforcement. For non-associative learning, we habituated foragers with S10%+P or S10%, followed by dishabituation tests with either a 50% sucrose solution paired (S50%+P) or unpaired (S50%) with pollen. Our results indicate that pollen foragers show lower performance than nectar foragers when conditioned with S10%. Interestingly, performance improves to levels similar to those of nectar foragers when pollen is included as a rewarding stimulus (S10%+P). In non-associative learning, pollen foragers tested with S10%+P displayed a lower degree of habituation than nectar foragers and a higher degree of dishabituation when pollen was used as the dishabituating stimulus (S10%+P). Altogether, our results support the idea that pollen and nectar honey bee foragers differ in their responsiveness to rewards, leading to inter-individual differences in learning that contribute to foraging specialization.
Relative importance of intensity and spectrum of artificial light at night in disrupting behavior of a nocturnal rodent
Authors: Longcore Travis , Villanueva Sophia Anne Marie B. , Nguyen-Ngo Kyle , Ghiani Cristina A. , Harrison Benjamin , Colwell Christopher S.
Published: June 2024

The influence of light spectral properties on circadian rhythms is of substantial interest to laboratory-based investigation of the circadian system and to field-based understanding of the effects of artificial light at night. The trade-offs between intensity and spectrum regarding masking behaviors are largely unknown, even for well-studied organisms. We used a custom LED illumination system to document the response of wild-type house mice (Mus musculus) to 1-h nocturnal exposure of all combinations of four intensity levels (0.01, 0.5, 5 and 50 lx) and three correlated color temperatures (CCT; 1750, 1950 and 3000 K). Higher intensities of light (50 lx) suppressed cage activity substantially, and consistently more for the higher CCT light (91% for 3000 K, 53% for 1750 K). At the lowest intensity (0.01 lx), mean activity was increased, with the greatest increases for the lowest CCT (12.3% increase at 1750 K, 3% increase at 3000 K). Multiple linear regression confirmed the influence of both CCT and intensity on changes in activity, with the scaled effect size of intensity 3.6 times greater than that of CCT. Activity suppression was significantly lower for male than for female mice. Assessment of light-evoked cFos expression in the suprachiasmatic nucleus at 50 lx showed no significant difference between high and low CCT exposure. The significant differences by spectral composition illustrate a need to account for light spectrum in circadian studies of behavior, and confirm that spectral controls can mitigate some, but certainly not all, of the effects of light pollution on species in the wild.
Η εξέλιξη της ορθοπαιδικής από ιδρύσεως του ελληνικού κράτους
Authors: Δρακουλάκης Εμμανουήλ
Published: June 2024

Η παρούσα διατριβή πραγματεύεται την εξέλιξη της ελληνικής ορθοπαιδικής όπως αυτή ενσωματώθηκε στην ελληνική επιστημονική ιατρική και έλαβε τα πρώτα της εμβρυϊκά βήματα με τη μορφή της σύγχρονης ιατρικής, σε χρόνο που συμπίπτει χρονικά με την ίδρυση του νεοελληνικού κράτους και ιδιαιτέρως με την έναρξη λειτουργίας της Ιατρικής Σχολής αμέσως μετά την καθίδρυση του Πανεπιστημίου Αθηνών έχοντας ως αφετηρία της την επιστημονική εξέλιξη της ορθοπαιδικής χειρουργικής στην Ευρώπη κατά τον 18ο και 19ο αιώνα. Έχοντας υπόψιν τα ανωτέρω εξετάζονται αναλυτικά όλες οι ιδέες σχετικά με την ορθοπαιδική όπως διατυπώθηκαν από τους Έλληνες ιατρούς του 19ου αιώνα, οι οποίοι στη συντριπτική τους πλειονότητα αποτελούν την πρώτη, δεύτερη και τρίτη γενιά Ελλήνων Καθηγητών της Ιατρικής Σχολής του Πανεπιστημίου Αθηνών. Συγκεκριμένα, διαπιστώνεται ότι αυτοί οι ιατροί ξεκινώντας από τον Ιωάννη Ολύμπιο και στη συνέχεια με σπουδαίες προσωπικότητες της χειρουργικής όπως ο Σπυρίδων Μαγγίνας, ο Παύλος Ιωάννου, ο Ευάγγελος Καλλιοντζής και στη διάρκεια του 20ού αιώνα ο Κωνσταντίνος Μέρμηγκας, Γεράσιμος Φωκάς, Νικόλαος Αλιβιζάτος, Μαρίνος Γερουλάνος και από τη δεκαετία 1930 ο Πέτρος Κόκκαλης και ο Ζαννής Καΐρης έθεσαν τις βάσεις για τη διαμόρφωση της ορθοπαιδικής που θα διδάσκονταν και θα ασκούνταν στην Ελλάδα. Καθώς η ιατρική εξελισσόταν διεθνώς η Ελλάδα ακολουθούσε κατά πόδας και γι' αυτό υπήρξε σταδιακή ανάπτυξη της ορθοπαιδικής χειρουργικής ξεπερνώντας τις απλές επεμβάσεις και φθάνοντας στο να εκτελούνται πλέον στην Ελλάδα σύνθετες και ειδικά στη σπονδυλική στήλη. Σε αυτό το πλαίσιο θα διακρίνουμε το επιστημονικό έργο του Ιωάννη Χρυσοσπάθη που θα αφιερωθεί σχεδόν αποκλειστικά στην ορθοπαιδική ώστε τελικά θα εκλεγεί ο πρώτος Έλληνας Καθηγητής Ορθοπαιδικής στην Ελλάδα, καθώς ο Γεράσιμος Φωκάς σχεδόν τριάντα χρόνια νωρίτερα είχε εκλεγεί Υφηγητής Ορθοπαιδικής παίδων στο Πανεπιστήμιο της Λιλ. Μεγάλη σημασία στο έργο του Ιωάννη Χρυσοσπάθη θα έχει το ενδιαφέρον και η προώθηση της ορθοπαιδικής ειδικά στην αποκατάσταση δυστροφιών και παραμορφώσεων, ανεξάρτητα από την αιτία τους, καταδεικνύοντας το βάθος της ιατρικής σκέψης του καθιστώντας αυτόν τον χειρουργό πρωτοπόρο στην άσκηση του πεδίου της ορθοπαιδικής στην Ελλάδα. Εξάλλου, η πρόοδος της ελληνικής ορθοπαιδικής, ιδιαίτερα από τη δεκαετία του 1930, θα έχει σημαντική εξέλιξη ώστε από τότε οι Έλληνες ιατροί να μελετούν συνθετότερα προβλήματα όπως, τα λοιμώδη αίτια των ορθοπαιδικών νοσημάτων και κυρίως η εισαγωγή του ανοσολογικού υποβάθρου στη μελέτη των αρθροπαθειών. Μετά τον Β' Παγκόσμιο Πόλεμο, η ελληνική ορθοπαιδική θα χαράξει την πορεία της παράλληλα με εκείνη που διαμορφώνεται στα διεθνή ερευνητικά κέντρα. Οι Έλληνες ορθοπεδικοί θα συγκαταλέγονται πλέον ανάμεσα στους πρωτοπόρους της χειρουργικής της σπονδυλικής στήλης, της αποκατάστασης των δυσμορφιών, της χειρουργικής της άκρας χείρας και της συγκόλλησης ακρωτηριασμένων άκρων.
Trayectoria de las necesidades psicológicas básicas en estudiantes secundarios de Entre Ríos, Argentina
Authors: Schönfeld Fátima Soledad , Mesurado Belén
Published: June 2024

El objetivo de este trabajo es conocer la trayectoria de las necesidades psicológicas básicas en estudiantes secundarios de Entre Ríos, Argentina, en tres momentos de su recorrido escolar. Para ello se realizó un diseño cuantitativo, siendo un estudio de tipo longitudinal. El muestreo utilizado fue no probabilístico intencional. La muestra se conformó por adolescentes escolarizados de Entre Ríos. Esta consistió en 313 sujetos para el primer tiempo, 280 para el segundo y 249 para el tercero. Las edades abarcaron desde los 12 hasta los 17 años. Respecto al instrumento, se utilizó la adaptación al contexto educativo de la Basic Psychological Needs Scale in General. Se realizaron análisis de modelos de curva de crecimiento latente; los hallazgos indican que la trayectoria de la autonomía puede ser explicada a través de un modelo de cambio cuadrático, la de la competencia mediante un modelo lineal y la de la relación de un modelo cuadrático.
The Impact of Geographic and Social Proximity on Physicians: Evidence from the Adoption of an Online Health Community
Authors: Wang Panpan , He Liuyi , Luo Jifeng , Wu Zhiyan , Zhang Han
Published: June 2024

Despite the increasing popularity of telehealth, the diffusion of online health communities lags behind because of the limited physician participation. The low adoption levels of telehealth could be attributed to the social environment rather than a baseline reluctance to adopt. By utilizing a panel data set of physicians’ adoption over eight years, we empirically investigate the impacts of geographically and socially close adopters and examined the interaction of proximity influences and competition in adoption. Our results suggest that positive effects of both geographic and social proximity influence on adoption when local competition among physicians on OHCs is low. The positive impact of socially close prior adopters increases with local competition, whereas that of geographically close prior adopters decreases with local competition. Therefore, online health communities could leverage proximity influence by incorporating information cues such as the cumulative adoption rates of close peers to facilitate physician adoption. However, the framing of information cues should consider interactions of competition and proximity influence. Platform managers need to balance the direct crowding-in effect of competition and the adverse moderating effect by which it diminishes the influence of geographic proximity, especially for low-title physicians. For high-title physicians, who are more independent, emphasize the usefulness of online platforms.
Herbal remedies as a potential cause of hypoadrenalism
Authors: Patel Mihir , Newell Rebecca , Hillier Matthew , Ramalingam Ramanan
Published: June 2024

A 37-year-old woman presented with nausea, vomiting and headache. She was found to be profoundly hyponatraemic with a sodium of 121 mmol/L, which deteriorated following a fluid challenge. An initial hyponatraemia screen identified adrenal insufficiency, with cortisol of 48 nmol/L. History confirmed she had been taking the herbal plant, ashwagandha. After 3 days of fluid restriction and steroid replacement, her sodium returned to normal (139 mmol/L). This article reviews the possible harmful effects of over-the-counter herbal remedies and highlights the importance of considering a wide differential diagnosis in patients presenting with non-specific symptoms.
PRP DIVA PORTELA: EXPERIÊNCIAS FORMATIVAS
Authors: Moraes Queiroz de Melo Tatiana , Damasceno de Jesus Débora , Leite Rodrigues Tainara , De Jesus Bacelar Joice Ellen , Sampaio Santos Joicy Elen , Regis Souza Ana Carolina , Pereira de Azevedo Freitas Denize
Published: June 2024

O presente relato de experiência tem por finalidade apresentar as experiências pedagógicas que foram vivenciadas por meio do Programa de Residência Pedagógica (PRP). Este programa intenciona o aperfeiçoamento da formação docente, promovendo a imersão dos graduandos de licenciaturas na educação básica. Especificamente, neste estudo, o trabalho foi desenvolvido com os Residentes do Curso de Licenciatura em
Educação Física da Universidade Estadual de Feira de Santana (UEFS).  A escola campo das intervenções foi o Colégio da Polícia Militar Diva Portela, localizado no município de Feira de Santana. As observações e intervenções foram desenvolvidas com turmas dos Anos Finais do Ensino Fundamental e as do Ensino Médio. Concluímos que os conteúdos da Educação Física são de suma importância no ambiente escolar contribuindo significativamente para a formação humana do estudante ao tematizar fatores sociais, ambientais, motores e históricos. Ainda destacamos que a imersão das Residentes no ambiente escolar possibilitou que as experiências pedagógicas, desde o planejamento ao desenvolvimento das aulas até a constatação dos desafios pedagógicos, potencializaram a construção de uma visão crítica e reflexiva, materializando-se como uma experiência enriquecedora para a formação docente de cada um dos envolvidos.
Der Islam auf dem Konzil von Basel (1431–1449)
Authors: Langeloh Jacob
Published: June 2024

Eine Studie mit Editionen und Übersetzungen unter besonderer Berücksichtigung des Johannes von Ragusa
Front Matters
Authors: Langeloh Jacob
Published: June 2024

Danksagung, Abkürzungen und Siglen der Textzeugen, Abbildungsnachweis
Gender, Commerce, and the Restoration Book Trade: Mapping the Bookscape of Hannah Wolley's The Ladies Directory (1661)
Authors: Pennell Sara
Published: June 2024

Abstract: This article provides the first account and analysis of the publication of Hannah Wolley (c.1622-c.in or after 1674), the prolific but understudied author of five different domestic manuals between 1661 and 1674. The publication of The Ladies Directory in 1661 and its reprinting in 1662 provide the context for an exploration of the opportunities and challenges facing a first-time female 'Authress' (as Wolley was described on the title page) being published. As a non-elite but educated working woman, Wolley did not fit the mould of her female published precursors, and nor did the format and contents of her texts. This study shows how Wolley and other stakeholders in the production of The Ladies Directory navigated a challenging period in English book production, through conceiving the book as the first instalment in a series of domestic texts that could be printed separately but bound together; and argues that she used print as but one strand of her commercial 'offer', alongside private tuition and selling readymade medications.
"Adapted to the Soldier's Pocket": Military Discipline, Religious Publishing, and the Power of Print Format during the US Civil War
Authors: Zehnder Madeline
Published: June 2024

Abstract: In this article, I consider the surge of pocket-sized books produced for use by Union soldiers during the US Civil War, investigating how publisher choices about print format intersected with military and civilian attempts to manage the health, conduct, and efficiency of soldiers at scale. As objects believed to exert intimate influence over readers' mental and physical habits, books designed for the pocket promised both to aid and to undermine the production of orderly military bodies in nineteenth-century America. Even as reformers and military officials feared the influence of pornography and fiction published in small, concealable formats, religious organizations including the American Tract Society proposed that pocket-sized books could enhance efforts to discipline soldiers' minds and bodies for military success, including by habituating soldiers to hold books instead of playing cards. Meanwhile, the 1863 entry of Black soldiers into the Union Army, which I consider later in this article, prompted variations on these practices that highlight the racialized nature of Civil War-era approaches to soldier discipline. If wartime responses to pocket-sized books show that print formats may accumulate cultural meaning, such responses also demonstrate how works for the soldier's pocket activated nineteenth-century fantasies of individual optimization and population-level control.
Dreams: Charcot's Last Words on Hysteria
Authors: Gelfand Toby
Published: June 2024

abstract: Jean-Martin Charcot (1825–1893), the leading neurologist of his time, is best remembered for his studies on hysteria presented in clinical lectures at the Paris Salpêtrière hospital. Developing the concept of traumatic male hysteria after accidents in which patients suffered slight physical damage led him to advance a psychological explanation for hysteria. Traumatic hysteria is the context for a close reading of Charcot's "last words" based upon a final unpublished lesson in 1893. This case history concerns a seventeen-year-old Parisian artisan whose various signs of hysteria developed following a dream in which he imagined himself the victim of a violent assault. Charcot identifies the dream/nightmare as the "original" feature determining traumatic hysteria. The dream sets in motion an overwhelming consciousness followed by a susceptibility to "autosuggestion" producing somatic signs of hysteria. Charcot's final lesson on dreams thus culminates his study of the psychological basis of traumatic hysteria.