Antibody-Drug Conjugates in Urothelial Cancer: From Scientific Rationale to Clinical Development.

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

Lavandula angustifolia Mill. inhibits high glucose and nicotine-induced Ca2+ influx in microglia and neuron-like cells via two distinct mechanisms.

Smoking remains a significant health problem in patients with type 2 diabetes mellitus. This study compared intracellular Ca2+ ([Ca2+]i) in microglia, neurons, and astrocytes in the presence of high glucose (HG) and nicotine and evaluated the effects of Lavandula angustifolia Mill. essential oil (LEO) on this process. [Ca2+]i concentrations were measured by monitoring the fluorescence of Fura-2 acetoxymethyl ester. Treatment with HG and nicotine significantly increased [Ca2+]i in both microglia and neurons through Ca2+ influx from extracellular sources. This increased Ca2+ influx in microglia, however, was significantly reduced by LEO, an effect partially inhibited by the Na+/Ca2+ exchanger (NCX) inhibitor Ni2+. Ca2+ influx in neuron-like cells pretreated with HG plus nicotine was also significantly decreased by LEO, an effect partially inhibited by the L-type Ca2+ channel blocker nifedipine and the T-type Ca2+ channel blocker mibefradil. LEO or a two-fold increase in the applied number of astrocytes attenuated Ca2+ influx caused by high glucose and nicotine in the mixed cells of the microglia, neuron-like cells and astrocytes. These findings suggest that LEO can regulate HG and nicotine-induced Ca2+ influx into microglia and neurons through two distinct mechanisms.

Immunomethylomic profiles of long-term head and neck squamous cell carcinoma survivors on immune checkpoint inhibitors.

Aim: This study addresses the challenge of predicting the response of head and neck squamous cell carcinoma (HNSCC) patients to immunotherapy. Methods: Using DNA methylation cytometry, we analyzed the immune profiles of six HNSCC patients who showed a positive response to immunotherapy over a year without disease progression. Results: There was an initial increase in CD8 T memory cells and natural killer cells during the first four cycles of immunotherapy, which then returned to baseline levels after a year. Baseline CD8 T cell levels were lower in HNSCC immunotherapy responders but became similar to those in healthy subjects after immunotherapy. Conclusion: These findings suggest that monitoring fluctuations in immune profiles could potentially identify biomarkers for immunotherapy response in HNSCC patients.

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[Pleural Metastasis of Lung Cancer Combined with Pleuroparenchymal Fibroelastosis: A Case Report]. / 흉막폐실질 íƒ„ë ¥ì„¬ìœ ì¦ê³¼ 동반된 폐암의 흉막 ì „ì´: 증례 ë³´ê³ .

Pleural metastasis is the most common cause of malignant diseases involving the pleura, and characterized by pleural effusion, nodules, and thickening. Pleuroparenchymal fibroelastosis (PPFE) is a disease characterized by apical pleural thickening and subjacent parenchymal fibrosis. We report a case of a 60-year-old male with lung cancer in the left lower lobe and underlying PPFE combined with left apical pleural metastasis. Initially, asymmetric left apical pleural thickening due to pleural metastasis was mistaken for PPFE. Additionally, we describe the imaging and histopathological findings of PPFE, including MRI findings.

Associations in cell type-specific hydroxymethylation and transcriptional alterations of pediatric central nervous system tumors.

Although intratumoral heterogeneity has been established in pediatric central nervous system tumors, epigenomic alterations at the cell type level have largely remained unresolved. To identify cell type-specific alterations to cytosine modifications in pediatric central nervous system tumors, we utilize a multi-omic approach that integrated bulk DNA cytosine modification data (methylation and hydroxymethylation) with both bulk and single-cell RNA-sequencing data. We demonstrate a large reduction in the scope of significantly differentially modified cytosines in tumors when accounting for tumor cell type composition. In the progenitor-like cell types of tumors, we identify a preponderance differential Cytosine-phosphate-Guanine site hydroxymethylation rather than methylation. Genes with differential hydroxymethylation, like histone deacetylase 4 and insulin-like growth factor 1 receptor, are associated with cell type-specific changes in gene expression in tumors. Our results highlight the importance of epigenomic alterations in the progenitor-like cell types and its role in cell type-specific transcriptional regulation in pediatric central nervous system tumors.

Identifying tumor type and cell type-specific gene expression alterations in pediatric central nervous system tumors.

Central nervous system (CNS) tumors are the leading cause of pediatric cancer death, and these patients have an increased risk for developing secondary neoplasms. Due to the low prevalence of pediatric CNS tumors, major advances in targeted therapies have been lagging compared to other adult tumors. We collect single nuclei RNA-seq data from 84,700 nuclei of 35 pediatric CNS tumors and three non-tumoral pediatric brain tissues and characterize tumor heterogeneity and transcriptomic alterations. We distinguish cell subpopulations associated with specific tumor types including radial glial cells in ependymomas and oligodendrocyte precursor cells in astrocytomas. In tumors, we observe pathways important in neural stem cell-like populations, a cell type previously associated with therapy resistance. Lastly, we identify transcriptomic alterations among pediatric CNS tumor types compared to non-tumor tissues, while accounting for cell type effects on gene expression. Our results suggest potential tumor type and cell type-specific targets for pediatric CNS tumor treatment. Here we address current gaps in understanding single nuclei gene expression profiles of previously under-investigated tumor types and enhance current knowledge of gene expression profiles of single cells of various pediatric CNS tumors.

Impact of Apolipoprotein E4 on the Locus Coeruleus Functional Connectivity in Preclinical Alzheimer's Disease.

Background: Recent interest has surged in the locus coeruleus (LC) for its early involvement in Alzheimer's disease (AD), notably concerning the apolipoprotein ɛ4 allele (APOE4). Objective: This study aimed to discern LC functional connectivity (FC) variations in preclinical AD subjects, dissecting the roles of APOE4 carrier status and amyloid-ß (Aß) deposition. Methods: A cohort of 112 cognitively intact individuals, all Aß-positive, split into 70 APOE4 noncarriers and 42 carriers, underwent functional MRI scans, neuropsychological assessments, and APOE genotyping. The research utilized seed to voxel analysis for illustrating LC rsFC discrepancies between APOE4 statuses and employed a general linear model to examine the interactive influence of APOE4 carrier status and Aß deposition on LC FC values. Results: The investigation revealed no significant differences in sex, age, or SUVR between APOE4 carriers and noncarriers. It found diminished LC FC with the occipital cortex in APOE4 carriers and identified a significant interaction between APOE4 carrier status and temporal lobe SUVR in LC FC with the occipital cortex. This interaction suggested a proportional increase in LC FC for APOE4 carriers. Additional notable interactions were observed affecting LC FC with various brain regions, indicating a proportional decrease in LC FC for APOE4 carriers. Conclusions: These findings confirm that APOE4 carrier status significantly influences LC FC in preclinical AD, showcasing an intricate relationship with regional Aß deposition. This underscores the critical role of genetic and pathological factors in early AD pathophysiology, offering insights into potential biomarkers for early detection and intervention strategies.

Alteration of DNA methyltransferases by eribulin elicits broad DNA methylation changes with potential therapeutic implications for triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) is an aggressive disease with limited treatment options. Eribulin, a chemotherapeutic drug, induces epigenetic changes in cancer cells, suggesting a unique mechanism of action. Materials & methods: MDA-MB 231 cells were treated with eribulin and paclitaxel, and the samples from 53 patients treated with neoadjuvant eribulin were compared with those from 14 patients who received the standard-of-care treatment using immunohistochemistry. Results: Eribulin treatment caused significant DNA methylation changes in drug-tolerant persister TNBC cells, and it also elicited changes in the expression levels of epigenetic modifiers (DNMT1, TET1, DNMT3A/B) in vitro and in primary TNBC tumors. Conclusion: These findings provide new insights into eribulin's mechanism of action and potential biomarkers for predicting TNBC treatment response.

Cumulative exposure to hypertriglyceridemia and risk of type 2 diabetes in young adults.

AIM: This study aimed to examine whether cumulative exposure to hypertriglyceridemia is associated with an increased risk of developing type 2 diabetes in young adults. METHODS: The study included 1,840,251 participants aged 20-39 years who had undergonefourconsecutiveannualhealth checkups and had no history of type 2 diabetes. Participants werecategorized into five groups (exposure score 0-4) based on the frequencies of hypertriglyceridemia diagnosis over a four-year period. The primary outcome was newly diagnosed type 2 diabetes. Exploratory analyses were performed for the different subgroups. RESULTS: During a follow-up period of 6.53 years, 40,286 participants developed type 2 diabetes. The cumulative incidence of type 2 diabetes significantly increased with higher exposure scores for hypertriglyceridemia (log-rank test, P < 0.001). The multivariable-adjusted hazard ratios for incident diabetes were 1.674 (95 % CI, 1.619, 1.732), 2.192 (95 % CI, 2.117, 2.269), 2.637 (95 % CI, 2.548, 2.73), and 3.715 (95 % CI, 3.6, 3.834) for participants with scores of 1-4, respectively, compared with those with an exposure score of 0. CONCLUSIONS: In this large-scale prospective cohort study of young adults, cumulative exposure to hypertriglyceridemia was significantly associated with an increased risk of type 2 diabetes, independent of lifestyle-related factors.

Risk of non-thyroidal autoimmune diseases in patients with Graves' disease: a nationwide retrospective cohort study.

OBJECTIVE: Graves' disease (GD) is a major autoimmune thyroid disorder and associated with non-thyroidal autoimmune disease (NTAD). We aimed to investigate the risk of NTAD in patients with GD compared with age- and sex-matched controls and to evaluate whether the risk differs between individuals with or without Graves' ophthalmopathy (GO). METHODS: This was a retrospective cohort study using data from the Korean National Health Claims database. We included 77 401 patients with GD (2,310 with GO) and 77 401 age- and sex-matched controls. Risk of NTAD were compared between the entire cohort and within the GD cohort. RESULTS: During a mean follow-up period of 9 years, NTAD developed in 12 341 (16.1%) patients in the GD cohort. Risk for systemic lupus erythematosus (SLE) [adjusted hazard ratio (aHR):1.15, 95% confidence interval (CI): 1.02-1.29], vitiligo (aHR: 1.24, 95% CI: 1.10-1.40), and alopecia areata (aHR: 1.11, 95% CI: 1.10-1.40) were higher in the GD cohort than in the control cohort. In the GD cohort, risk for SLE (aHR: 1.60, 95% CI: 1.11-2.33), Sjogren's syndrome (aHR: 1.89, 95% CI: 1.30-2.74), and ankylosing spondylitis (aHR: 1.53, 95% CI: 1.08-2.17) were higher in the GO group than in the non-GO group. CONCLUSION: This study demonstrated an increased risk of SLE, vitiligo and alopecia areata in patient with GD. In the GD cohort, patients with GO had an increased risk of SLE, Sjogren's syndrome and ankylosing spondylitis. These findings suggest that importance of implementing a strategy for early detection of NTAD based on the presence of GO.

Differential Regulation of Intracisternally Injected Angiotensin II-Induced Mechanical Allodynia and Thermal Hyperalgesia in Rats.

The present study examined the underlying mechanisms of mechanical allodynia and thermal hyperalgesia induced by the intracisternal injection of angiotensin (Ang) II. Intracisternal Ang II injection decreased the air puff threshold and head withdrawal latency. To determine the operative receptors for each distinct type of pain behavior, we intracisternally injected Ang II receptor antagonists 2 h after Ang II injection. Losartan, an Ang II type 1 receptor (AT1R) antagonist, alleviated mechanical allodynia. Conversely, PD123319, an Ang II type 1 receptor (AT2R) antagonist, blocked only thermal hyperalgesia. Immunofluorescence analyses revealed the co-localization of AT1R with the astrocyte marker GFAP in the trigeminal subnucleus caudalis and co-localization of AT2R with CGRP-positive neurons in the trigeminal ganglion. Intracisternal pretreatment with minocycline, a microglial inhibitor, did not affect Ang II-induced mechanical allodynia, whereas L-α-aminoadipate, an astrocyte inhibitor, significantly inhibited Ang II-induced mechanical allodynia. Furthermore, subcutaneous pretreatment with botulinum toxin type A significantly alleviated Ang II-induced thermal hyperalgesia, but not Ang II-induced mechanical allodynia. These results indicate that central Ang II-induced nociception is differentially regulated by AT1R and AT2R. Thus, distinct therapeutic targets must be regulated to overcome pain symptoms caused by multiple underlying mechanisms.

Prevalence and trends in mono- and co-infection of COVID-19, influenza A/B, and respiratory syncytial virus, January 2018-June 2023.

Objectives: This study aimed to determine the impact of the COVID-19 pandemic on the overall prevalence and co-infection rates for COVID-19, influenza A/B, and respiratory syncytial virus in a large national population. Methods: We conducted a retrospective review of 1,318,118 multi-component nucleic acid amplification tests for COVID-19, influenza A/B, and RSV performed at Labcorp® sites from January 2018 to June 2023, comparing positivity rates and co-infection rates by age, sex, and seasonality. Results: In 2021-2023, 1,232 (0.10%) tested positive for COVID-19 and influenza A/B, 366 (0.03%) tested positive for COVID-19 and RSV, 874 (0.07%) tested for influenza A/B and RSV, and 13 (0.001%) tested positive for COVID-19, influenza A/B, and RSV. RSV positivity rates were particularly higher in Q2 and Q3 of 2021 and in Q3 of 2022. Higher influenza A positivity proportions were found in Q4 of 2021 and again in Q2 and Q4 of 2022. Influenza B positivity had been minimal since the start of the pandemic, with a slight increase observed in Q2 of 2023. Conclusion: Our findings highlight the need for adaptability in preparation for upper respiratory infection occurrences throughout the year as we adjust to the COVID-19 pandemic due to the observed changes in the seasonality of influenza and RSV. Our results highlight low co-infection rates and suggest heightened concerns for co-infections during peaks of COVID-19, influenza, and RSV, which may perhaps be reduced.