bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of spleen volume on post-allogenic hematopoietic transplant outcomes in myelofibrosis: Utility of 3D volumetrics in splenomegaly.
Authors: Haseeb Rafay , Yang Dongyun , Motarjem Pejman , Al Malki Monzr M. , Aldoss Ibrahim , Amanam Idoroenyi Usua , Otoukesh Salman , Forman Stephen J. , Marcucci Guido , Rahmanuddin Syed , Ali Haris
Published: June 2024

6558

Background: Splenomegaly is a hallmark of myelofibrosis, thought to be correlated with graft failure and worsened overall survival in transplant patients. Past studies have utilized manual spleen measurement, potentially affecting accuracy. Using 3D volume can more precisely measure spleen size. Hence, the true impact of splenomegaly on transplant outcomes remains unclear. In this retrospective study, we examined myelofibrosis patients who underwent HCT and, using 3D volumetrics, analyzed the impact of splenomegaly and volume reduction over time on post HCT outcomes. Methods: This retrospective study included 130 City of Hope myelofibrosis patients with pre HCT imaging (2004–2023). Patients were divided into pre HCT spleen volume of >3000 cc and <3000 cc, with >3000 cc considered massive splenomegaly. Spleen volume was measured using Vitrea 3D volumetric software. For each patient, depending on imaging available, volume was measured 0-3 months pre HCT, 3-6 months, 6-9 months, and 9-12 months post HCT with corresponding volume reduction calculations. Pre HCT spleen volume was also temporally correlated with several post HCT outcomes. Results: Median age at HCT was 60 (17-75), and 95% of patients received the Fludarabine/Melphalan conditioning regimen. Median spleen volume pre HCT was 1150 cc (41-6695 cc). Sixteen patients measured >3000cc, and 114 patients measured <3000cc. Median spleen volume 3-6 months post HCT was 661 cc (80-1731 cc) with a median 48% volume reduction. The data suggests that majority of volume reduction occurred during this time (table). Five-year overall survival (OS) was 72.8%. Relapse was 11.0% at 1 year and 14.7% at 5 years. NRM at 5 years was 17.3%. ANC engraftment peaked at 28 days at 92.3%. Pre HCT spleen volume (<1000 cc, 1000-2000 cc, >2000 cc) did not have a significant impact on OS (P = 0.992), disease free survival (P = 0.783), relapse (P = 0.187), NRM (P = 0.627), or ANC Engraftment (P = 0.526). There was a statistically insignificant downward trend for platelet engraftment (P = 0.162). For patients with or without massive splenomegaly (>3000cc), there was no significant effect with any of the analyzed post HCT outcomes. Conclusions: This retrospective study includes an analysis of spleen volume by 3D volumetrics, a more accurate measurement of spleen size, and whether it significantly impacts post HCT outcomes. Our data analysis demonstrates that splenomegaly, massive or not, does not significantly impact transplant outcomes for patients receiving a reduced intensity conditioning regimen.[Table: see text]
Assessment of carcinoembryonic antigen-related cell adhesion molecule 5 expression by immunohistochemistry in real-world clinical samples of non-small cell lung cancer.
Authors: Hsu Ying-Han Roger , Almutrafi Amna , Hueniken Katrina , Tsao Ming Sound
Published: June 2024

e20013

Background: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is an emerging target of antibody-drug conjugate therapy for non-small cell lung cancer (NSCLC). High expression of CEACAM5 has been reported in approximately 25% of patients with lung adenocarcinoma (Lefebvre AM, et al. Lung Cancer. 2023; 184:107356). However, CEACAM5 expression has not been systematically examined in a real-world patient population with NSCLC. In this study, we evaluated our experience in the assessment of CEACAM5 expression by immunohistochemistry (IHC) in routinely diagnosed clinical samples. Methods: We assessed the expression of CEACAM5 by IHC on clinical biopsy/resection samples of consecutively diagnosed NSCLC from September 2022 to June 2023 at our institution, using the anti-CEACAM5 clone 769 antibody assay protocol developed for tusamitamab ravtansine clinical trials. Only cases adequate for PD-L1 22C3 and Oncomine Comprehensive Assay v3 NGS assay were included. CEACAM5 expression was scored independently by three pathologists based on the method proposed by Lefebvre et al. Expression levels were categorized as high (≥ 50% tumor cells at ≥ 2+ intensity), moderate (1–49% tumor cells at ≥ 2+ intensity), and negative (0 or 1+ intensity). Interrater reliability was assessed by Kendall’s coefficient of concordance (KCC) and Fleiss’ Kappa. Discordant classification was reviewed with the final classification achieved by consensus. Association with PD-L1 TPS and NGS results was determined by Chi-squared test. Results: This study cohort consisted of 150 consecutively diagnosed NSCLC, including 133 adenocarcinomas and 17 squamous cell carcinomas. The samples were derived from both primary (n = 138) and metastatic sites (n = 12). Both membranous and cytoplasmic CEACAM5 expression was observed in neoplastic cells, but was consistently absent in nonneoplastic cells. The prevalence of consensus high CEACAM5 membranous expression was 21% (n = 32) overall, 20% in primary (n = 28) and 33% (n = 4) in metastatic sites. The level of interrater agreement across all categories was moderate (KCC = 0.77). Interrater agreement between high CEACAM5 expression versus moderate/negative categories combined was also moderate (Kappa = 0.60). Challenging features included the determination of staining intensity and mixed membranous and cytoplasmic staining pattern, and cases near the cut-offs of the defined categories. CEACAM5 expression was not associated with PD-L1 TPS (p = 0.42) or EGFR mutations (p = 0.44). Conclusions: Our data showed that approximately 20% of routinely diagnosed clinical NSCLC samples had high CEACAM5 expression by IHC. The interrater reliability on the determination of high CEACAM5 expression was moderate among the three pathologists. We highlighted the challenging aspects in the evaluation of this biomarker.
Comparison and performance of three plasma next-generation sequencing assays versus tissue testing for the detection of actionable driver mutations in advanced non-squamous non-small cell lung carcinoma.
Authors: Hofman Paul , Bontoux Christophe , Lacoux Caroline , Inaudi Rignol Guylène , Goffinet Samantha , Lespinet Virginie , Bordone Olivier , Tanga Virginie , Allegra Maryline , Garnier Georges , Boutros Jacques , Benzaquen Jonathan , Marquette Charles Hugo , Ilie Marius , Hofman Veronique
Published: June 2024

e20018

Background: Liquid biopsy (LB) is a useful tool for the detection of actionable mutations in advanced non-squamous non-small cell lung cancer (NS-NSCLC) at progression. However, the clinical benefits of integrating both LB and tissue biopsy (TB)-based genomic profiling at diagnosis of NS-NSCLC remain uncertain. Methods: We tested three commercially available next-generation sequencing (NGS) gene panel assays in circulating cell-free DNA (cfDNA) using replicate sets of 85 LB samples from advanced NS-NSCLC patients at baseline and compared the results with matched TB for the detection of tier IA/B (AMP/ASCO/CAP classification) alterations. We used methylation testing of cfDNA to assess the tumor fraction (TF). We correlated molecular data with clinico-pathological features and follow-up data. Results: All TB-based NGS results were interpretable. 5 LB-based NGS results for one assay were not performed due to the material exhaustion. Tier IA/B gene alteration was detected by LB-based NGS and TB-based NGS in 18 to 23 (21 to 27%) patients and in 35 (41%) patients, respectively. The positive percent agreement of each LB-based NGS assay method compared with TB-based NGS assay ranged from 51% to 68%. The incremental add provided by first LB-based NGS ranged from 0 to 23% versus 25 to 45% for first TB-based NGS, depending on the LB-based NGS assay. It includes one EGFR uncommon mutation, 9 MET amplifications and 2 HER2 amplifications detected by LB-based NGS assays that were not detected by TB-based NGS. Overall agreement between the three LB-based NGS assays was 44%. Hybrid-capture based assay detects 14 MET/HER2 CNVs, two METex14 skipping mutation and two ALK fusions that were not detected by amplicon-based assay. Amplicon-based assay detects one uncommon EGFR mutation, one KRAS non-G12C and one ALK fusion that were not detected by hybrid-capture based assay. 64 LB samples were tested for cfDNA methylation. Positive predictive value and negative predictive value of the detection of TF by cfDNA methylation profiling was 90% and 92%, respectively. The only false-negative result of TF evaluation by cfDNA methylation profiling was observed for a variant with a cfDNA VAF < 1%. Correlation analyses with clinicopathological data are ongoing. Conclusions: While concordance with tissue is relatively high, the incremental add provided by LB-based NGS at diagnosis of advanced NS-NSCLC compared to TB-based NGS is limited and greatly varies according to the sequencing method used. Thus, LB-based NGS at diagnosis of NSCLC can be used as a complement of TB-based NGS or as an alternative when tissue is not available.
Genomic characteristics of tumour necrosis in lung squamous cell carcinoma.
Authors: Zhang Longfeng , Lin Gen , Zhong Qiaofeng , Wu Lin , Zhao Jun , Sun Jianguo , Huang Cheng
Published: June 2024

e20030

Background: Tumor necrosis and cavity on enhanced chest CT are common hallmarks of lung squamous cell carcinoma (LUSC). However, the genetic characteristics of necrosis on CT scan remain unclear. This study aims to elucidate the genetic landscape of LUSC with tumor necrosis. Methods: We implemented transcriptome and whole-exome sequencing to analyze early postoperative LUSC specimens. They were classified into necrosis and non-necrosis group based on preoperative enhanced chest CT. Subsequently, the genomic landscape between the two groups were compared. To substantiate our findings, we further employed immunohistochemistry and analysis of a clinical cohort as comprehensive methods of validation. Results: In study cohort (65 samples), the necrosis group (n = 37) showed a higher number and length of copy number variations (CNVs) and elevated Genomic Instability Index (GII) compared to the non-necrosis group (n = 28). Transcriptome sequencing revealed increased hypoxic hallmarks and activation of 11 fundamental metabolic pathways in the necrosis group. Endothelial cells were observably fewer, but matrix remodeling score was higher in the necrosis group. Here, the decreased activity of several immune-related pathways, such as antigen processing and presentation, natural killer cell-mediated cytotoxicity, etc, were notably suppressed in the necrosis group. Immunohistochemistry indicated that the expressions of hypoxy-related genes (HIF-1, NDRG1), proliferation-related genes (ki-67) and angiogenesis related genes (CD31) in necrosis group were significantly higher than those in non-necrosis group. In the clinical validation cohort, we enrolled 538 advanced LUSC patients from 25 medical centers receiving systemic treatment, categorized into chemotherapy (n = 270) and ICIs (n = 268) groups. A notable difference in progression-free survival (PFS) was observed in the ICIs group, with patients without tumor necrosis or cavity exhibiting significantly longer PFS (8.7 vs. 6.5 months; HR 0.67; 95% CI 0.42–0.63; p < 0.001). Multivariate Cox analysis identified necrosis or cavity as an independent predictor of reduced PFS (HR 0.68; 95% CI, 0.51-0.9; p = 0.007). Conclusions: LUSC with necrosis is distinguished by increased genomic instability, hypoxia, enhanced tumor proliferation, matrix remodeling, and an immunosuppressive tumor microenvironment. Baseline chest CT findings of tumor necrosis or cavities may serve as negative predictors for the efficacy of ICIs treatment in LUSC.
Multi-omics profiling the genomic origin and adeno-squamous transdifferentiation mechanism in adenosquamous carcinoma.
Authors: Zheng Xinlong , Li Chao , Jiang Kan , Zhou Zhipeng , Bai Jing , Long Feng , Yan Jianfeng , Lin Gen
Published: June 2024

e20032

Background: Adenosquamous carcinoma (ASC) represents a rare subtype (0.4-4%) of non-small-cell lung cancer (NSCLC), with its multi-omic landscape yet to be fully elucidated. This study aims to explore the genomic origins and molecular mechanisms of adeno-squamous transdifferentiation in lung ASC through comprehensive multi-omics. Methods: We analyzed 69 samples from 31 lung ASC patients, including 16 FFPE samples with microdissected paired adenocarcinoma (AC) and squamous cell carcinoma (SCC) components, and additionally, incorporated pure Lung Adenocarcinoma (LUAD, n = 51) and pure Squamous Cell Carcinoma (LUSC, n = 28) for comparative analysis. Techniques included whole-exome sequencing, whole-genome methylation profiling, transcriptomics, single-cell RNA sequencing, and spatial transcriptomics. Results: AC and SCC exhibited similar genomic mutation landscapes, indicating a common genomic origin for AD and SCC. The SCC component in ASC displayed higher homologous recombination repair deficiency (HRD) and a notable 16p13.3 deletion in 31% of ASC transformations. Differential methylation analysis highlighted TP63's lower methylation in SCC, correlating negatively with RNA expression (P < 0.001), indicative of methylation-driven regulation. DMR binding motif analysis revealed hypo-methylation in p63, p53, and AP-1 motifs, and hyper-methylation in MKX2-1, FOXA1/2 motifs (P < 0.05). The transition from AC to SCC in ASC was marked by upregulated MYC signaling, proliferation, and DNA repair, with EMT changes not methylation-driven. Metabolic pathways were upregulated, and EMT/KRAS pathways downregulated in SCC compared to LUSC. Immune infiltration in LUAD-AC-ASC transformation showed an initial increase and subsequent decrease, transitioning from immune-infiltrated and immune-excluded to immune-desert phenotypes. IL36G of the IL1 family was highly expressed in the SCC component and strongly correlated with the squamous marker P63 (Pearson r = 0.72, P < 0.001). Single-cell RNA-seq data demonstrated a significant increase in IL36G in squamous cells of lung ASC. In vivo models showed adeno-squamous differentiation in adenocarcinoma cells expressing IL36G. Conclusions: This study provides a comprehensive multi-omic insight into the complex genomic and epigenomic landscape of ASC, highlighting a shared genomic origin and distinct molecular mechanisms in the adeno-squamous transdifferentiation process. The findings, particularly the role of TP63 methylation and IL36G expression in the SCC component, offer novel insights into the molecular heterogeneity of ASC. These results not only deepen our understanding of ASC but also pave the way for future investigations into targeted therapies that could potentially exploit these molecular distinctions for more effective treatment strategies in ASC.
Lung and bronchus cancer in young females: Exploring sex disparities across diverse racial and ethnic groups in the U.S. (2000-2020).
Authors: Hechter Sharon , Kanukuntla Anish Kumar , Eliachevsky Christina , Ji Sophia , Appiah Jennifer , Alnaser Ibrahim , Nair Ambica , Greenberg David B.
Published: June 2024

e20048

Background: Lung and bronchus cancer incidence rates have been reported to be higher among females than males under the age of 50, particularly after 2004. The first e-cigarette device emerged in 2003, raising questions about its potential impact on cancer incidence in females compared to males and its connection to the sudden rise in female cases. This study aims to investigate sex differences in cancer incidence across diverse racial and ethnic groups, aiming to determine whether these variations stem from biological factors or unexplored environmental exposures. Methods: Cancer incidence data from the Surveillance, Epidemiology, and End Result (SEER) program (2000-2020) were utilized to analyze female-to-male incidence rate ratios (FM IRR) for young-onset lung and bronchus cancer diagnosed before the age of 50. The data was stratified by race and ethnicity (non-Hispanic White, non-Hispanic Black, non-Hispanic Asian/Pacific Islander, American Indian/Alaskan Native, and Hispanic) and age-standardized to the 2000 U.S. population. Results: In the period from 2000 to 2020, 41,066 patients with lung and bronchus cancer under the age of 50 were identified. Incidence trends showed a consistent decrease each year, reaching the lowest rates in 2020 (2.1 per 100,000 cases) and the highest in 2000 (4.9 per 100,000 cases). Males accounted for 49.4% (20,303), while females constituted 50.6% (20,763). Despite the overall declining trend, FM IRR steadily increased post-2004, exhibiting a constant rise between 2005 and 2020. Non-Hispanic White comprised 65.9% of the cases, with the second and third largest groups being Non-Hispanic Black (15.3%) and Hispanic (9.62%). Incidence rates were highest among non-Hispanic Black (4.9 per 100,000 cases), followed by non-Hispanic White (4.2 per 100,000 cases), and lowest in the Hispanic population (1.6 per 100,000 cases). Young-onset lung and bronchus cancer diagnosed before age 50 showed a female predominance after 2004, with the Hispanic population having the highest FM IRR between 2000 and 2020 (1.13), followed by Non-Hispanic American Indian/Alaska Native (1.09) and Non-Hispanic White (1.02). There was a lower FM IRR among Non-Hispanic Black and Non-Hispanic Asian/Pacific Islander (0.83) and (0.96), respectively. Conclusions: The FM IRR for young-onset lung and bronchus cancer exhibited variations among racial and ethnic groups, with the highest rates observed among the Hispanic population. This study was limited by the absence of data on smoking habits and other environmental factors. Further research is needed to investigate the influence of e-cigarettes and other environmental factors on the incidence of lung and bronchus cancer, considering variations by sex.
Multimodal risk stratification of non-metastatic lung adenocarcinoma using AI on histology and immunohistochemistry slides.
Authors: Adjadj Benjamin , Bannier Pierre-Antoine , Papadakis Andreas , Fournier Nancy , Rayes Roni , Marza Reem , Srivastava Archana , Agulnik Jason S. , Spicer Jonathan , Fiset Pierre-Olivier , Wang Hangjun , Schutte Kathryn , Spatz Alan
Published: June 2024

e20083

Background: While immunohistochemistry (IHC) slides are commonly used to assess the presence of actionable biomarkers, the recent advances in artificial intelligence (AI) focus exclusively on hematoxylin and eosin (H&E) slides. Nonetheless, many IHC slides, potentially rich in prognostic information, remain underexplored for risk stratification and outcome prediction. Our study aims to assess the complementarity of H&E and IHC slides through the development of a multimodal prognostic AI model for lung adenocarcinoma patients. Methods: We collected 1 H&E slide, 8 IHC slides (PD-L1, FOXP3, HELA2, CD3, CD4, CD8, CD163, KI67), and 2 double-stained slides (PDL1-CD163 and CD3-CD163) from 245 resected patients with lung adenocarcinoma at two different hospitals (median OS = 54.0 months [11.3 - 138.0]). Patients underwent various adjuvant treatments (chemotherapy n=92; immunotherapy n=4; other n=36; no treatment n=152). We cross-validated 11 AI models (one model per staining) to predict overall survival in these patients. We used Harell’s C-index and the 70-month cumulative AUC to evaluate the performance of our models. To assess their stratification power, each model’s predictions were split into high-risk and low-risk populations to compute a Hazard Ratio and a log-rank test p-value. Subsequently, a Cox proportional hazards model aggregated the predictions of the 11 models to compute a final risk score. We performed a grid search to find the combination of markers yielding the highest C-index. We calculated the hazard ratios to determine each biomarker's predictive value. Results: The H&E model was the best unimodal model, with a C-index of 0.69 [0.67 - 0.71]. The best-performing multivariate model was obtained by combining the risk scores from univariate models in a Cox regression using H&E, CD8, PD-L1, HELA2, and FOXP3 slides, reaching a C-index of 0.71 [0.69 - 0.73] (Table). We found that the predictions from H&E (HR = 1.39; P = 0.03) and PD-L1 (HR = 1.17; P = 0.04) were significantly associated with survival. Conclusions: By significantly improving patient stratification with non-metastatic lung adenocarcinoma, our multivariate model proves that some IHC markers contain complementary proteomic information to H&E slides. Consequently, this study paves the way for developing more comprehensive risk assessment tools from H&E and IHC stainings. [Table: see text]
A preliminary study on the timing of radiotherapy for chemoimmunotherapy in oligometastatic non-small-cell lung cancer with negative driver genes.
Authors: Ma YingYing , Liao Ziyi
Published: June 2024

e20084

Background: Local radiotherapy (LRT) is reported to provide durable local and distant disease control for oligometastatic non-small cell lung cancer (NSCLC) in accumulating evidence, but research on the optimal initial time point remains scarce. We conducted a study to preliminarily evaluate the timing of radiotherapy for chemoimmunotherapy in Oligometastatic Non-small-cell lung cancer with negative driver genes. Methods: 50 patients diagnosed with Oligometastatic Non-small-cell lung cancer with negative driver genes who were treated with chemoimmunotherapy and radiotherapy were retrospectively recruited between January 2018 and October 2023. They were divided into two groups: one early to initiate radiotherapy group (≤2 cycles of immunotherapy, EAR group) and one deferred radiotherapy group (>2 cycles of immunotherapy, DEF group). The clinical efficacy and adverse reactions were compared between the two groups. Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier curves, the Cox proportional hazard model was used to find out predictors of PFS and OS. Results: The tumor control rates had no significance was observed when comparing these two groups (50.0% and 26.9%, respectively, p = 0.093). The PFS in the RAE group was significantly higher than that in the DEF group (median PFS: 12.2 months vs 5.3 months, P<0.05). The OS in two groups were no significance (median OS: 20.5months vs 23.1months, P>0.05). The results of the Cox multivariate regression analysis revealed that the number of metastatic lesions and organs were independent prognostic factors for PFS. The number of metastatic lesions and organs, maintain therapy were independent predictors associated with OS. All patients well tolerated the treatments. Conclusions: Early initiation of local radiotherapy resulted in better PFS and no significant increase in adverse reactions was observed.
Incidence trends and factors affecting survival in mucinous adenocarcinoma of the lung: Insights from SEER data.
Authors: Aimalla Nikhila , Kesireddy Meghana , Yadukumar Lekha
Published: June 2024

e20090

Background: Lung cancer is the second most common cancer in terms of incidence and the leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) accounts for 80 to 85% of cases. Adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma are the main subtypes of NSCLC. Mucinous adenocarcinoma is the least common subtype of lung adenocarcinoma with poor prognosis. Our study aims to identify demographics, incidence trends, and factors impacting overall survival (OS) in mucinous adenocarcinoma of the lung. Methods: We conducted a retrospective cohort analysis utilizing the Surveillance, Epidemiology, and End Results (SEER) database to investigate patients diagnosed with mucinous adenocarcinoma of the lung between the years 2000 and 2020. Demographics, treatment data were characterized using descriptive statistics. The Cox proportional regression analysis was used to identify the factors that impact the OS. Results: Between 2000-2020, a total of 7,953 patients were diagnosed with mucinous adenocarcinoma of the lung. The highest incidence of mucinous adenocarcinoma was in older adults, accounting for 67% of all cases. Females had a higher incidence rate at 53.6%. Caucasians comprised the majority of patients at 83.1%, followed by blacks at 8.8%. The majority of patients, 89.3% resided in urban areas, and 43.6% had annual incomes exceeding $75k. Most of the patients were married at 58.2%. The incidence trends revealed a significant increase from 2000 to 2020. The incidence rates were: 15.76% (2000 -2004), 16.37% (2005 -2009), 31.08% (2010 - 2014), and 36.79% (2015-2020). However, the survival rates improved over time (See table). Among the demographic factors: adults, females, Asian/ Natives/ & other races combined, urban residence, higher annual income (> $75k), and married status had better OS outcomes than their counterparts. Among disease stages, localized disease had the best, while regional disease had a better OS than distant disease. In terms of treatment, surgery was associated with better OS; interestingly, receipt of radiation or chemotherapy was not associated with better OS. The HRs of all these factors are shown in Table. Conclusions: Our study, the largest to date on mucinous adenocarcinoma of the lung, demonstrated a rising incidence yet with improved OS rates from 2000-2020. Our findings shed light on the demographics and other factors influencing OS in this rare subtype of NSCLC. [Table: see text]
Tazemetostat in combination with topotecan and pembrolizumab in patients with recurrent small cell lung cancer.
Authors: Desai Parth Anil , Takahashi Nobuyuki , Lissa Delphine , Nichols Samantha , Sciuto Linda , Abel Melissa Lauren , Schroeder Brett , Schultz Christopher , Steinberg Seth M. , Pinkiert Danielle , Vilimas Rasa J , Thomas Anish
Published: June 2024

TPS8130

Background: Small-cell lung cancer (SCLC) is the most fatal type of lung cancer characterized by exquisite chemo-sensitivity at diagnosis and chemoresistance at relapse. Despite a highly mutated genome, patients with SCLC derive little benefit from immunotherapy. EZH2 (enhancer of zeste homolog 2) is a master epigenetic regulator of SCLC neuroendocrine cell fate and plasticity. EZH2 inhibition 1) promotes upregulation of Schlafen 11 (SLFN11) which irreversibly blocks replication in response to DNA damaging agents and 2) enhances intrinsic immune signaling, leading to constitutive MHC I recovery, sensitizing resistant SCLC models to DNA damaging chemotherapy and immunotherapy. Tazemetostat is a selective oral EZH2 inhibitor. Methods: This is an investigator-initiated, NCI Cancer Therapy Evaluation Program (CTEP) sponsored, phase I dose escalation and dose expansion study which will evaluate safety and tolerability of combination of tazemetostat with topotecan, a selective TOP1 inhibitor, and programmed cell death protein 1 (PD-1) inhibitor antibody pembrolizumab. Adult patients with relapsed/recurrent SCLC after at least platinum doublet (limited stage-SCLC) or chemo-immunotherapy (extensive stage-SCLC) and ECOG performance 0-1 are eligible. The regimen design involves a 7-day “run-in” of oral tazemetostat BID followed by 21-day cycles of tazemetostat (1-21 days), intravenous (IV) topotecan (day 1-5) and IV pembrolizumab (Day 1). The dose escalation cohort aims to determine safety and optimal doses of tazemetostat and topotecan (with standard dose of pembrolizumab) using a 3+3 design by assessing for dose limiting toxicities. The dose expansion cohort aims to assess safety, tolerability and preliminary efficacy of the combination in 15 additional patients with relapsed SCLC. The study involves collection of mandatory biopsies at pre-treatment and post-treatment (cycle 1) to gain insights into mechanism of action and resistance of the combination using single cell and spatial transcriptomic approaches. For more questions regarding enrollment and eligibility please contact Rasa.vilimas@nih.gov or anish.thomas@nih.gov . Clinical trial information: NCT05353439 .
The use of stem cells in the treatment of diabetes mellitus and its complications - review
Authors: Ochyra Łukasz , Łopuszyńska Anna
Published: June 2024

Introduction and purpose Diabetes is a disease resulting from impaired action or secretion of insulin. The number of patients currently amounts to approximately 422 million, and approximately 1.5 million deaths per year are directly attributed to this disease. Diabetes significantly reduces the quality of life and, if poorly controlled, can lead to serious complications. Mesenchymal stem cells are multipotent cells capable of differentiation. They have the ability to self-renew and have a modulating function. There are reports that they can be used in the treatment of this disease. The aim of the review was to present a new method of therapy and their possible effects. Material and methods The review was based on articles obtained from PubMed scientific database in the years 2015-2023, using the following keywords: diabetes mellitus, stem cells, diabetes complications. Results Implanted stem cells are able to transform into cells that produce and secrete insulin, and also enable better glycemic control. They can alleviate chronic inflammation and reduce fibrosis. Taking into account the complications that occur during long-term diabetes, the use of stem cells may be associated with improving the function of specific organs and tissues such as the kidneys, heart, eyes and nerves. Studies also report a positive effect of these cells on the healing process of wounds and ulcers. Conclusions Stem cells are a promising object of analysis. They can control glycemia and have a positive effect on the functioning of the kidneys, heart, eyes and nerves, and accelerate wound healing, but further, extensive research is needed to assess the effectiveness and safety of this therapy.
correlation between diabetes mellitus and depression
Authors: Madera Magdalena , Mazur Sylwia , Mazur Agata , Bizan Aleksy , Nagórska Emilia , Marcinkowski Krzysztof , Strus Karolina , Kublińska Aleksandra , Zdunek Roksana , Dąbrowska Natalia
Published: June 2024

Depression is the most prevalent mental health condition. It’s estimated that nearly 5% of adults suffer from this disorder globally. Depression is marked by ongoing sadness and a loss of interest or pleasure in activities that were once enjoyable or fulfilling. It can also lead to disruptions in sleep and eating patterns. Common symptoms include fatigue and difficulty concentrating.
According to WHO diabetes is a chronic, metabolic disease characterized by elevated levels of blood glucose which leads to the damage of the heart, blood vessels, eyes, kidneys and nerves. Nowadays the occurrence of diabetes mellitus, obesity and depression is getting higher and higher. Both conditions stand as prominent health issues in today’s society. Recent pandemic, wars, problems of the current world can cause depression and anxiety disorders. The fast-paced nature of our lives, work-life balance issues, sedentary habits, and time constraints can lead to opting for fast food and neglecting a healthy diet. People with diabetes are more prone to experiencing depression. Moreover, a significant portion of cases remains underdiagnosed.
Una aproximación al derecho a la verdad como un derecho autónomo en el Sistema Interamericano de Derechos Humanos
Authors: Luna Ramírez Gabriela , Pérez Amaya Natalia , López-Cárdenas Carlos Mauricio
Published: June 2024

Teniendo en cuenta lo anterior, el objetivo del presente capítulo es abordar el concepto del derecho a la verdad y los instrumentos en los que se encuentra contenido, con el fin de establecer la relación que tiene con otros derechos y así determinar si en el Sistema Interamericano de Protección de los Derechos Humanos puede ser visto como un derecho autónomo, especialmente en situaciones de desaparición forzada de personas.
Parejas del mismo sexo y familia: protección contra la discriminación basada en la orientación sexual en el marco del derecho internacional de los derechos humanos
Authors: Quintero Martínez Rocío Liliana
Published: June 2024

Para ello, este capítulo se estructura en tres secciones. En la primera sección se examina la protección a las personas lgtb en el derecho internacional de los derechos humanos y la orientación sexual como categoría sospechosa para otorgar tratamientos jurídicos distintos a parejas del mismo sexo en la jurisprudencia de los órganos de los tratados de Naciones Unidas y de las cortes regionales de derechos humanos. En la segunda parte se analiza la extensión del derecho a la familia a las parejas del mismo sexo y sus hijos. Finalmente, en la última sección se realiza un examen detallado del derecho al matrimonio para parejas del mismo sexo en el marco internacional de protección de los derechos humanos
Las comisiones de memoria y verdad ante el reto de narrar la atrocidad masiva: una forma de reconstruir el pasado de violencia, paz y reconciliación de América Latina
Authors: Luna Blanco Tania
Published: June 2024

El capítulo que se presenta tiene como objetivo central responder a la pregunta: ¿de qué manera se han narrado los conflictos en América Latina al interior de las comisiones de memoria y verdad judicial creadas en distintos contextos de posconflicto? Centra sus esfuerzos en dos países con procesos transicionales posdictaduras: Argentina y Chile; y uno con acuerdo de paz para el posconflicto: Colombia. El elemento que nos permite comparar contextos tan disímiles viene dado por las iniciativas de memoria y verdad judicial que se han presentado en estos escenarios. Los casos seleccionados son interesantes porque permiten, aun desde sus limitaciones, generar una radiografía de las historias que se están contando sobre violencia, paz y reconciliación desde los centros oficiales de producción de la memoria y la verdad en América Latina, explorando las posibilidades de estas narraciones para reconocer a las víctimas y resignificar las violencias, así como su potencial de erigirse en peligrosas historias oficiales del conflicto latinoamericano.
Panorama de la deforestación y el tráfico de especies silvestres en Colombia: una mirada desde la experiencia de los funcionarios públicos
Authors: Güiza-Suárez Leonardo , Correa-Muñoz Lina Katerine
Published: June 2024

Distintos investigadores coinciden al afirmar que tales desafíos tienen que ver con dificultades al interior de las instituciones gubernamentales mismas. Por lo tanto, el propósito de este capítulo es presentar un diagnóstico de las principales dificultades institucionales (en términos de normativa, logística, capacitación, etc.) que enfrentan funcionarios públicos en Colombia a la hora de hacer investigaciones, operativos de incautación o procesos sancionatorios en eventos de tala ilegal y tráfico de especies tal como estas son experimentadas por los funcionarios públicos. Tal diagnóstico se realiza con base en los resultados de una investigación cuyo propósito consistió en evidenciar la relación entre las actividades de tala ilegal y tráfico ilegal de especies, por un lado, y los grupos armados al margen de la ley que operan en Colombia, por otro, para el periodo 2014-2019.
Barreras para el cumplimiento de la normatividad ambiental
Authors: Salas-Pérez Yuliana , Páez-Delgado Daniel Ricardo
Published: June 2024

Este capítulo tiene por objetivo describir las barreras para el cumplimiento de la normatividad ambiental en Colombia, para ello, se identifican las problemáticas ambientales en las zonas de mayor importancia ecológica y se analizan procesos de cumplimiento o incumplimiento de la normatividad ambiental, finalmente se proponen estrategias que permitan superar las barreras.
On the Profitability of Loyalty
Authors: Lei Ying , Shen Ji , Yang Ei , Zhai Xin
Published: June 2024

This paper characterizes repeat-purchase loyalty in a dynamic competitive environment and discusses the profitability of different types of loyalty driven by switching costs and positive brand preferences.
Risks to Human Capital
Authors: Ebrahimian Mehran , Wachter Jessica A.
Published: June 2024

We build a model with inalienable human capital, in which investors finance individuals who can potentially become skilled. Although investment in skill is always optimal, it does not take place in some states of the world, due to moral hazard. In intermediate states of the world, individuals acquire skill; however outside investors and individuals inefficiently share risk. We show that this simple moral hazard problem, combined with risk aversion of individuals and outside investors, amplifies the equity premium, lowers the risk-free rate, and leads to disaster states that fall especially heavily on some agents but not on others. We show that the possibility of disaster states distorts risk prices and affects wealth inequality, even under calibrations in which they never occur in equilibrium.

This paper was accepted by Lukas Schmid, finance.

Funding: M. Ebrahimian acknowledges funding from the Swedish House of Finance.

Supplemental Material: The data files are available at https://doi.org/10.1287/mnsc.2022.03068 .
Innovation Disclosures and the Design of Technology Acquisition Contracts: Evidence from the American Inventors Protection Act
Authors: Reuer Jeffrey J. , Bisui Sandip , Chondrakis George
Published: June 2024

Material adverse change (MAC) clauses and contingent earnouts are important contractual mechanisms used to protect acquirers from the risk of adverse selection. Yet, the extant literature has not sufficiently explored the antecedents of their use, in particular within the context of technology acquisitions. In this study, we take advantage of the passage of the American Inventors Protection Act (AIPA), which disseminated information through the publication of patent applications, to explore the impact of innovation disclosures on the design of technology acquisition contracts. Consistent with the view that an increase in the availability of information related to the broader technological landscape reduces the need for contractual protections in acquisition contracts, our analysis demonstrates that deals disproportionately affected by AIPA have less expansive MAC clauses and are less likely to feature contingent earnouts. These results provide new evidence linking the use of MAC clauses and earnouts with acquisitions subject to information frictions.
Integrating Geolocational Features with ZY-1E Satellite and Multibeam Data Using Random Forest Algorithm for Bathymetry Inversion in the Yangtze River Nantong Channel
Authors: zhongqiang wu , wei Shen , xin li , siwen fang , mao zhihua , wu shulei
Published: June 2024

Accurate bathymetry information is crucial for safe navigation and efficient management of the Yangtze River Channel, a vital shipping corridor in China. Traditional bathymetric surveying methods are time-consuming and labor-intensive, limiting their application in large-scale and real-time monitoring. This study proposes a novel approach for bathymetry inversion in the Yangtze River Nantong Channel by integrating geolocational features from the ZY-1E satellite with high-resolution multibeam data using a random forest algorithm. The Random Forest with Longitude/Latitude (RF-Lon./Lat.) model, which incorporates geographical information, outperformed conventional methods, achieving an R² of 0.57, MAE of 1.99m, and RMSE of 2.96m. The successful application of the RF-Lon./Lat. model highlights the effectiveness of integrating geolocational features with machine learning algorithms for accurate bathymetry inversion in the complex and turbid waters of the Yangtze River Channel. This innovative approach offers a promising solution for precise and efficient water depth estimation, which is essential for various applications in the Yangtze River Basin, including channel management, waterway maintenance, and hydrological studies. The insights gained from this study contribute to the growing body of knowledge on the application of machine learning and remote sensing techniques for bathymetric mapping in complex river environments, particularly in the context of the Yangtze River Channel.
The prevalence and risk of mortality associated with intradialytic hypertension among patients with end-stage kidney disease on haemodialysis: A systematic review and meta-analysis
Authors: Adejumo Oluseyi Ademola , Edeki Imuetinyan Rahsida , Oyedepo Dapo Sunday , Yisau Olawale Elijah , Ige Olanrewaju Olumide , Ekrikpo Inyeneabasi Udeme , Moussa Ayman Sabri , Palencia Hansel , Noubiap Jean Jacques , Ekrikpo Udeme Ekpenyong
Published: June 2024

Introduction

Intradialytic hypertension (IDHTN) is a common but less frequently recognised complication of haemodialysis. However, it is associated with increased overall mortality in patients on haemodialysis. This systematic review and meta-analysis aimed to determine the prevalence of IDHTN and associated mortality risk in the global haemodialysis population.

Method

A systematic search of PubMed and EMBASE was undertaken to identify articles with relevant data published between 1990 and 2023. The pooled prevalence of IDHTN in the global haemodialysis population was determined using the DerSimonian-Laird random-effects meta-analysis. The pooled hazards ratio for mortality in patients with IDHTN was also computed from the studies that reported mortality among haemodialysis patients with IDHTN. The study protocol was registered with PROSPERO (CRD42023388278).

Results

Thirty-two articles from 17 countries were included, with a pooled population of 127,080 hemodialysis patients (median age 55.1 years, 38.2% females). Most studies had medium methodological quality (53.1%, n = 17). The overall pooled prevalence of IDHTN was 26.6% [(95% CI 20.2–33.4%), n = 27 studies, I2 = 99.3%, p<0.001 for heterogeneity], with significant differences depending on the definition used. The pooled proportion of haemodialysis sessions with IDHTN was 19.9% [(95% 12.5–28.6%, n = 8 studies, I2 = 99.3%, p<0.001 for heterogeneity)] with significant differences across the different definition criteria. The p-value for the Begg test was 0.85. The median pre-dialysis blood pressure was not significantly associated with IDHTN. The pooled hazard ratio for mortality was 1.37 (95% CI 1.09–1.65), n = 5 studies, I2 = 13.7%, and p-value for heterogeneity = 0.33.

Conclusion

The prevalence of IDHTN is high and varies widely according to the definition used. A consensus definition of IDHTN is needed to promote uniformity in research and management. The increased mortality risk forecasted by IDHTN highlights the need for optimal blood pressure control in patients on hemodialysis.
Theoretical design of blockchain-based traceability for organic egg supply chains according to regulation (EU) 2018/848
Authors: Zülch Florian , Holle Martin , Hofmann Andreas
Published: June 2024

The use of blockchain technology to establish food traceability chains has the potential to provide transparent information of food stuffs along the entire supply chain and also aid in the documentation or even execution of official food control processes. Particularly in instances where analytical methodologies cannot provide definitive data for food control questions under study, the certificate-based approach of a traceability chain may offer a way of regulatory control for state authorities. Given the rising importance of organic produce and the high share of eggs among the organic produce in the European Union as well as the new EU regulation on organic products and labelling that came into force in 2022, we analyze here how the control of egg production type and marketing standards can be represented within a blockchain-based traceability chain such as to maximize the traceability in compliance with the current relevant EU regulations. Intended for the use by the official food control authorities, a traceability chain for organically produced eggs in the EU would need to be implemented as a permissioned blockchain, since only select entities are allowed to participate. By combining a proof of authority consensus mechanism with issuance of soulbound tokens, we effectively suggest a ‘proof of soulbound authority’ consensus process. The soulbound tokens are issued throughout the administrative chain from the European Commission down to the official food control authorities in individual member states that ultimately certify the control bodies for organic produce. Despite the general limitation of not providing unambiguous proof of the organic status of individual products, the concept discussed here offers advantages with respect to allocation of authority at EU level and therefore might have positive effects beyond the traceability chain.
Teachers’ competence: How to protect teachers’ mental health from the burden caused by students’ private in-class use of technical devices?
Authors: Brailovskaia Julia , Duscha Anna-Lena , Kreyelkamp Greta M. , Margraf Jürgen
Published: June 2024

The current study investigated how students’ private in-class use of technical devices is associated with teachers’ mental health. Data of 361 teachers from primary and secondary schools in Germany were assessed via online surveys. The present cross-sectional results show a positive association between burden caused by the students’ private in-class use of technical devices and teachers’ depression symptoms. Both were negatively linked to teachers’ positive mental health (PMH) and teachers’ competence in handling students’ private in-class use of technical devices. In a moderated mediation analysis, the association between burden and depression symptoms was mediated by PMH. Teachers’ competence moderated the link between PMH and depression symptoms. Specifically, the higher the competence, the weaker the relationship between both variables. Thus, the protective effect of teachers’ competence could be especially important in persons with low PMH. Competence training in handling students’ use of technical devices is discussed as a potential step that could protect teachers’ mental health.
Comparative evaluation of HPV genotyping: A study on the performance concordance between Anyplex II HPV28 detection and Linear Array genotyping tests in nationwide studies in Brazil
Authors: Bandeira Isabel Cristina , Comerlato Juliana , Bessel Marina , Fernandes Bruna Vieira , Mota Giana , Villa Luisa Lina , de Souza Flávia Moreno Alves , Pereira Gerson Fernando Mendes , Wendland Eliana Marcia
Published: June 2024

Background

Advances in laboratory techniques for HPV diagnosis necessitate a thorough assessment of the efficiency, replicability, sensitivity, and specificity of those methods. This study aims to validate and compare HPV detection/genotyping using the Anyplex™ II HPV28 Detection assay (Seegene) assay and the Linear Array HPV Genotyping test (Roche Diagnostics) on genital samples for use in epidemiological studies.

Methods

From 6,388 penile and cervical DNA samples collected in the POP-Brazil, 1,745 were randomly selected to be included in this study. The samples were submitted to HPV detection and genotyping following the manufacturers’ protocols. DNA was genotyped using the Anyplex™ II HPV28 Detection kit (Seegene), and the results were compared to those obtained using the Linear Array HPV Genotyping test (Roche Diagnostics). Concordance of HPV genotyping results was assessed by the percentage agreement and Cohen’s kappa score (κ).

Results

The agreement between the two methodologies was deemed good for HPV detection (κ = 0.78). Notably, Anyplex™ II HPV28 demonstrated enhanced capability in detecting a broader spectrum of genotypes compared to Linear Array.

Conclusion

Anyplex™ II HPV28 exhibited comparable results to the Linear Array assay in clinical specimens, showcasing its potential suitability for a diverse array of research applications requiring the detection and genotyping of HPV. The study supports the utility of Anyplex™ II HPV28 as an effective tool for HPV screening in epidemiological studies, emphasizing its robust performance in comparison to established diagnostic tests.