Biomarkers Of Response Research Articles

The third generation AKR1C3-activated prodrug, ACHM-025, eradicates disease in preclinical models of aggressive T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that expresses high levels of the enzyme aldo-keto reductase family 1 member C3 (AKR1C3). To exploit this finding, we developed a novel prodrug, ACHM-025, which is selectively activated by AKR1C3 to a nitrogen mustard DNA alkylating agent. We show that ACHM-025 has potent in vivo efficacy against T-ALL patient-derived xenografts (PDXs) and eradicated the disease in 7 PDXs. ACHM-025 was significantly more effective than cyclophosphamide both as a single agent and when used in combination with cytarabine/6-mercaptopurine. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo. The in vivo efficacy of ACHM-025 directly correlated with AKR1C3 expression levels, providing a predictive biomarker for response. Together, our work provides strong preclinical evidence highlighting the potential of ACHM-025 as a targeted and effective therapy for aggressive forms of T-ALL.

A Comparative Study of Methyl-BEAMing and Droplet Digital PCR for MGMT Gene Promoter Hypermethylation Detection.

Background: O-6-methylguanine-DNA methyltransferase is responsible for the direct repair of O6-methylguanine lesions induced by alkylating agents, including temozolomide. O-6-methylguanine-DNA methyltransferase promoter hypermethylation is a well-established biomarker for temozolomide response in glioblastoma patients, also correlated with therapeutic response in colorectal cancer. Objectives: The ARETHUSA clinical trial aims to stratify colorectal cancer patients based on their mismatch repair status. Mismatch repair-deficient patients are eligible for treatment with immune checkpoint inhibitors (anti-PDL-1), whereas mismatch repair-proficient samples are screened for O-6-methylguanine-DNA methyltransferase promoter methylation to identify those suitable for temozolomide treatment. Methods: In this context, a subset of ARETHUSA metastatic colorectal cancer samples was used to compare two different techniques for assessing O-6-methylguanine-DNA methyltransferase hypermethylation: Methyl-BEAMing, a highly sensitive digital PCR approach that combines emulsion PCR and flow cytometry, and droplet digital PCR, a more automated procedure that enables the rapid, operator-independent analysis of a large number of samples. Results: Our study clearly demonstrates that the results obtained using Methyl-BEAMing and droplet digital PCR are comparable, with both techniques showing similar accuracy, sensitivity, and reproducibility. Conclusions: Digital droplet PCR proved to be an efficient method for detecting gene promoter methylation. However, the Methyl-BEAMing method has proved more sensitive for detecting low quantities of DNA.

Ocular biometric responses to simulated polychromatic defocus.

Evidence from human studies of ocular accommodation and studies of animals reared in monochromatic conditions suggest that chromatic signals can guide ocular growth. We hypothesized that ocular biometric response in humans can be manipulated by simulating the chromatic contrast differences associated with imposition of optical defocus. The red, green, and blue (RGB) channels of an RGB movie of the natural world were individually incorporated with computational defocus to create two different movie stimuli. The magnitude of defocus incorporated in the red and blue layers was chosen such that, in one case, it simulated +3 D defocus, referred to as color-signed myopic (CSM) defocus, and in another case it simulated -3 D defocus, referred to as color-signed hyperopic (CSH) defocus. Seventeen subjects viewed the reference stimulus (unaltered movie) and at least one of the two color-signed defocus stimuli for ∼1 hour. Axial length (AL) and choroidal thickness (ChT) were measured immediately before and after each session. AL and subfoveal ChT showed no significant change under any of the three conditions. A significant increase in vitreous chamber depth (VCD) was observed following viewing of the CSH stimulus compared with the reference stimulus (0.034 ± 0.03 mm and 0 ± 0.02 mm, respectively; p = 0.018). A significant thinning of the crystalline lens was observed following viewing of the CSH stimulus relative to the CSM stimulus (-0.033 ± 0.03 mm and 0.001 ± 0.03 mm, respectively; p = 0.015). Differences in the effects of CSM and CSH conditions on VCD and lens thickness suggest a directional, modulatory influence of chromatic defocus. On the other hand, ChT responses showed large variability, rendering it an unreliable biomarker for chromatic defocus-driven responses, at least for the conditions of this study.

Complete response to fifth-line anti-PD-1 rechallenge in fumarate hydratase-mutated papillary renal cell carcinoma

Fumarate hydratase (FH) mutated papillary renal cell carcinoma is an aggressive variant of kidney cancer that poorly responds to conventional targeted therapies and immunotherapy. Here, we present the 10-year follow-up of a heavily pre-treated patient with several lines of therapy, achieving a remarkable complete response to anti-PD-1 rechallenge. In addition, we highlight a common immune-related adverse event of anti-PD-1, eosinophilia, as a possible biomarker of response and using TCGA data analysis, provide proof-of-concept for tumor expression of the eosinophil-related gene SIGLEC8, as a promising powerful predictor of prognosis for papillary renal cell carcinoma patients.

ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis.

Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and ACE2 expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune competent mice. Mass cytometry by time of flight (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1-7)/Mas receptor axis. The lower CCL5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.

CTR-DB 2.0: an updated cancer clinical transcriptome resource, expanding primary drug resistance and newly adding acquired resistance datasets and enhancing the discovery and validation of predictive biomarkers.

Drug resistance is a principal limiting factor in cancer treatment. CTR-DB, the Cancer Treatment Response gene signature DataBase, is the first data resource for clinical transcriptomes with cancer treatment response, and meanwhile supports various data analysis functions, providing insights into the molecular determinants of drug resistance. Here we proposed an upgraded version, CTR-DB 2.0 (http://ctrdb.ncpsb.org.cn). Around 190 up-to-date source datasets with primary resistance information (129% increase compared to version 1.0) and 13 acquired-resistant datasets (a new dataset type), covering 10 856 patient samples (111% increase), 39 cancer types (39% increase) and 346 therapeutic regimens (26% increase), have been collected. In terms of function, for the single dataset analysis and multiple-dataset comparison modules, CTR-DB 2.0 added new gene set enrichment, tumor microenvironment (TME) and signature connectivity analysis functions to help elucidate drug resistance mechanisms and their homogeneity/heterogeneity and discover candidate combinational therapies. Furthermore, biomarker-related functions were greatly extended. CTR-DB 2.0 newly supported the validation of cell types in the TME as predictive biomarkers of treatment response, especially the validation of a combinational biomarker panel and even the direct discovery of the optimal biomarker panel using user-customized CTR-DB patient samples. In addition, the analysis of users' own datasets, application programming interface and data crowdfunding were also added.

A microarray-based IgE-molecular mimicry index (IgE-MMI): A biomarker for disease severity, clinical phenotypes, and therapeutic response in atopic dermatitis?

The role of autoimmune IgE responses in atopic dermatitis (AD) is highly debated. While IgE targeting self-proteins has been extensively studied, IgE responses induced by human-homologous exogenous molecular allergens (HEMAs) remains less understood. To investigate whether IgE antibody responses to HEMAs are associated with AD, its severity, and response to dupilumab. We enrolled 3325 participants with a history of allergic diseases, including 577 (17.3%) diagnosed with AD. Serum IgE antibodies against 183 exogenous allergenic molecules were measured using the IgE microarray (Allergy Explorer-ALEX-2®, MADX, Vienna). Based on international classification criteria, participants were stratified by AD severity and clinical phenotypes. For each patient, we developed an 'IgE molecular-mimicry index' (IgE-MMI), calculated from IgE reactivity to a panel of five HEMA protein families: arginine kinase, enolase (ENO), cyclophilin (CYP), lipocalin, and MnSOD. Logistic regression was employed to assess the association between IgE to HEMAs or IgE-MMI and AD, its severity, and response to dupilumab. IgE sensitization to most HEMAs (32/48, 67%), but only to a small fraction of non-HEMAs (3/135, 2.2%), was significantly more common in patients with severe AD compared to other patient groups. The IgE-MMI was positive in 295/2748 (10.7%) of allergic patients without AD, and in 58/283 (20%), 52/134 (39%), and 86/160 (54%) of patients with remitting, moderate, or severe AD, respectively. It was strongly associated with specific phenotypes, such as flexural dermatitis (OR 8.4, 95% CI: 6.3-11.2), head and neck dermatitis (OR: 16.5, 95% CI: 7.4-37.2), and generalized eczema (OR: 8.6, 95% CI: 4.9-15.6). Poor response to dupilumab was associated with IgE antibodies to ENO (OR: 22.7, 95% CI: 1.7-302.9), but inversely associated with IgE antibodies to MnSOD (OR: 0.1, 95% CI: 0.02-0.8) and NPC-2 from dust mites (OR: 0.1, 95% CI: 0.01-0.9). IgE microarrays are useful for broadly assessing IgE to HEMAs in allergic patients. IgE reactivity to HEMAs and a positive IgE-MMI may serve as valuable biomarkers for severe AD, its clinical phenotypes, and the response to dupilumab.

Intestinal subtype as a biomarker of response to neoadjuvant immunochemotherapy in locally advanced gastric adenocarcinoma: insights from a prospective phase II trial.

Neoadjuvant immunochemotherapy (NAIC) markedly induces pathologic regression in locally advanced gastric adenocarcinoma (GAC). However, specific biomarkers are still lacking to effectively identify the beneficiary patients for NAIC. A prospective, single-arm, phase II study was conducted to treat locally advanced GAC with NAIC (NCT05515796). Correlation between clinicopathological characteristics and neoadjuvant efficacy was investigated. Bulk RNA-seq data from 104 samples (from 75 patients in two independent cohorts) and scRNA-seq data from 105 treatment-naïve GACs were comprehensively analyzed to decipher the association of epithelial and microenvironmental characteristics and clinical responses. The pre-specified primary endpoints were achieved: pathological complete regression (pathCR) rate was 30%, major pathological regression (MPR) rate was 43%, while the regimen was well tolerated. Analysis of baseline clinical-pathological parameters revealed the intestinal subtype of Lauren's classification as a key feature stratifying patients with increased sensitivity to NAIC. Mechanistically, an increased pool of DNA damage repair (DDR)-active cancer cells and enrichment of CLEC9A+ dendritic cells (DCs) in the tumor microenvironment were associated with enhanced responsiveness of the intestinal subtype GAC to NAIC. More importantly, an intestinal-subtype specific signature model was constructed by the machine learning algorithm NaiveBayes via integrating the transcriptomic features of both DDR-active cancer cells and CLEC9A+ DCs, which accurately predicted the efficacy of NAIC in multiple independent GAC cohorts. Intestinal subtype is a histological biomarker of enhanced sensitivity of GAC to NAIC. The Intestinal-subtype specific signature model is applicable to guide NAIC for patients with locally advanced GAC.

Metabolomics for the identification of biomarkers in endometriosis.

Endometriosis affects the quality of life in women during their reproductive years, causing immense pain and can result in infertility. It is characterized by inflammation and the growth of the endometrium outside the uterine cavity. Metabolomics has the potential to resolve the major bottleneck of endometriosis which is delay in diagnosis due to the invasive diagnostic approach.In this review, the author has summarized the identified biomarkers of endometriosis from different bodily fluids. Metabolomics promises a non-invasive diagnostic approach for endometriosis that could aid in earlier diagnosis and prognosis. Patients with endometriosis keywords were searched in correspondence with the assigned keywords, including metabolomics from PubMed, from its inception to Dec 2023. The relevant studies from this search were extracted and included in the study. This article provides information regarding metabolomics studies in endometrisis. We demonstrated that metabolomics is about to change the world of endometriosis by analyzing and detecting the diagnosis, prognosis, mortality and treatment response biomarkers.

Toxicokinetics and responses of multiple biomarkers of sediment-associated fluoroquinolones in an ecologically important freshwater snail Bellamya aeruginosa

Fluoroquinolones (FQs) have the propensity to accumulate in sediments once introduction into aquatic environments, thereby posing potential threats to benthic organisms, yet the ecotoxicity of sediment-associated FQs remains unclear. In this study, the toxicokinetics and responses of multiple biomarkers in Bellamya aeruginosa, exposed to the three commonly used FQs (norfloxacin, NOR; ciprofloxacin, CIP; levofloxacin, LEVO) at environmentally relevant concentrations were investigated under sediment exposure scenario. The results revealed that FQs were effectively ingested by B. aeruginosa from sediments, CIP showing the highest bioaccumulation (180.59 μg/kg), followed by NOR (74.49 μg/kg) and LEVO (36.02 μg/kg). CIP exhibiting a highest uptake rate constant (Ks) (4.64 g/(g.d)) and the lowest elimination rate constant (Ke) (0.05 g/(g.d)). The descending order of biological half-life is as follows: CIP (13.62 d), LEVO (8.14 d), and NOR (6.83 d). NOR induced the activity of superoxide dismutase, catalase, and glutathione-S-transferase while CIP and LEVO depressed their activities and increased malondialdehyde content, indicating a more pronounced oxidative damage to B. aeruginosa caused by CIP and LEVO than NOR. Furthermore, all three FQs were found to induce DNA damage and elevate acetylcholinesterase activity, suggesting distinct genotoxic and neurotoxic effects. Interestingly, despite its low bioaccumulation potential, LEVO exhibited high toxicity towards B. aeruginosa. These findings enhance our understanding of the ecotoxicity of FQs in sediments, providing further evidence of their potential ecological risks.

Disruption of RNA Splicing Increases Vulnerability of Cells to DNA-PK Inhibitors.

DNA-dependent protein kinase (DNA-PK) is a key effector of non-homologous end joining (NHEJ)-mediated double-strand break (DSB) repair. Since its identification, a substantial body of evidence has demonstrated that DNA-PK is frequently overexpressed in cancer, plays a critical role in tumor development and progression, and is associated with poor prognosis in cancer patients. Recent studies have also uncovered novel functions of DNA-PK, shifting the paradigm of the role of DNA-PK in oncogenesis and renewing interest in targeting DNA-PK for cancer therapy. To gain genetic insight into the cellular pathways requiring DNA-PK activity, we used a CRISPR/Cas9 screen to identify genes in which defects cause hypersensitivity to DNA-PK inhibitors. We identified over one hundred genes involved in DNA replication, cell cycle regulation, and RNA processing that promoted cell survival when DNA-PK kinase activity was suppressed. This gene set will be useful for characterizing novel biological processes that require DNA-PK activity and identifying predictive biomarkers of response to DNA-PK inhibition in the clinic. We also validated several genes from this set and reported previously undescribed genes that modulate the response to DNA-PK inhibitors. In particular, we found that compromising the mRNA splicing pathway led to marked hypersensitivity to DNA-PK inhibition, providing a possible rationale for the combined use of splicing inhibitors and DNA-PK inhibitors for cancer therapy.

A comprehensive investigation of associations between cell death pathways and molecular and clinical features in pan-cancer.

Regulated cell death (RCD) pathways play significant roles in tumorigenesis. However, systematic investigation into correlations between RCD and various molecular and clinical features, particularly anti-tumor immunity and immunotherapy response in pan-cancer remains lacking. Using the single-sample gene set enrichment analysis, we quantified the activities of six RCD pathways (apoptosis, autophagy, ferroptosis, cuproptosis, necroptosis, and pyroptosis) in each cancer specimen. Then, we explored associations of these six RCD pathways with tumor immunity, genomic instability, tumor phenotypes and clinical features, and responses to immunotherapy and targeted therapies in pan-cancer by statistical analyses. Our results showed that the RCD (except autophagy) activities were oncogenic signatures, as evidenced by their hyperactivation in late stage or metastatic cancer patients, positive correlations with tumor proliferation, stemness, genomic instability and intratumor heterogeneity, and correlation with worse survival outcomes in cancer. In contrast, autophagy was a tumor suppressive signature as its associations with molecular and clinical features in cancer shows an opposite pattern compared to the other RCD pathways. Furthermore, heightened RCD (except cuproptosis) activities were correlated with increased sensitivity to immune checkpoint inhibitors. Additionally, elevated activities of pyroptosis, autophagy, cuproptosis and necroptosis were associated with increased drug sensitivity in a broad spectrum of anti-tumor targeted therapies, while the elevated activity of ferroptosis was correlated with decreased sensitivity to numerous targeted therapies. RCD (except autophagy) activities correlate with unfavorable cancer prognosis, while the autophagy activity correlate with favorable clinical outcomes. RCD (except cuproptosis) activities are positive biomarkers for anti-tumor immunity and immunotherapy response.

Neutrophil-to-Lymphocyte Ratio as a Biomarker for Clinical Response After Autologous Hematopoietic Stem Cell Transplantation in Systemic Sclerosis.

Systemic sclerosis is a complex disease that affects various target organs, making it difficult to assess response and determine remission or relapse. A baseline Neutrophil-to-Lymphocyte Ratio (NLR) >2.95 is associated with severe progressive skin and lung disease and decreased 5-year survival in systemic sclerosis (SSc). However, it is unknown whether NLR changes in response to treatment. To retrospectively evaluate NLR changes as a biomarker for treatment response in SSc. Progressive diffuse SSc patients who were treated with autologous hematopoietic stem cell transplantation (AHSCT group), with combination therapy of rituximab and mycophenolate mofetil (combination group) or CAR-T cell therapy (CAR-T group) were recruited, along with healthy controls (HC group). NLR, modified Rodnan Skin Score (mRSS) and forced vital capacity (FVC)% predicted were repeatedly assessed over 2 years. Fifteen patients were recruited in the AHSCT group, 15 in the combination group, and six patients in the CAR-T group. Baseline mean NLR was high (>2.95) in AHSCT, combination groups, and CAR-T compared with HC. All treatment arms showed a statistically significant decrease in mRSS values and an increase in FVC% at each time point up to 12 months. In a linear mixed model, NLR significantly decreased up to 24 months only in the AHSCT group. NLR correlated with mRSS and FVC exclusively in the AHSCT group. NLR increased above 3 in two patients who experienced a relapse after AHSCT. NLR is a simple biomarker that correlated with outcome measures in SSc following AHSCT, but not with conventional therapy or CAR-T therapy. It is suggested that a decrease in NLR following AHSCT may indicate remission, whereas an increase may be associated with exacerbation. Further research is needed to validate these novel findings.

Somatic mutational landscape reveals mutational signatures and significantly mutated genes of cancer immunotherapeutic outcome and sex disparities.

Currently developed molecular markers can predict the effectiveness of cancer immunotherapy and screen beneficiaries to some extent, but they are not stable enough. Therefore, there is an urgent need for discovering novel biomarkers. At the same time, sex factor plays a vital role in the response to immunotherapy, so it is particularly important to identify sex-related molecular indicators. We integrated a pan-cancer cohort consisting of 2348 cancer patients who received immune checkpoint inhibitors and targeted sequencing. Using somatic mutation profiles, we identified mutational signatures, molecular subtypes, and frequently mutated genes, and analyzed their relationships with immunotherapeutic outcomes. We also explored sex disparities of determined biomarkers in response to treatments. We found that male patients exhibited better immunotherapy outcomes and higher tumor mutational burden. A total of seven mutational signatures were identified, among which signatures 1 and 3 were associated with worse immunotherapy outcomes, while signatures 2 and 6 correlated with better outcomes. Gender-based analysis revealed that mutational signature 1 continued to show a worse immunotherapy outcome in female patients, whereas signature 6 demonstrated a better outcome in male patients. Based on mutational activities, we identified four potential molecular subtypes with gender differences and relevance to treatment outcomes. PI3K-AKT, RAS signaling pathways, and 68 significantly mutated genes were identified to be associated with immunotherapy outcomes, with nine genes (i.e., ATM, ATRX, DOT1L, EP300, EPHB1, NOTCH1, PBRM1, RBM10, and SETD2) exhibiting gender differences. Finally, we discovered co-mutated gene pairs and TP53 p.R282W mutations related to treatment outcomes, highlighting their gender-specific differences. This study identified several molecular biomarkers related to cancer immunotherapy outcomes in terms of mutational signatures, molecular subtypes, and mutated genes, and explored their gender-relatedness in order to provide clues and basis for clinical treatment efficacy evaluation and patient selection.

Sex Differences in Physiological Responses to a National Collegiate Athletic Association Division I Soccer Season.

McFadden, BA, Walker, AJ, Cintineo, HP, Bozzini, BN, Sanders, DJ, Chandler, AJ, and Arent, SM. Sex differences in physiological responses to a National Collegiate Athletic Association Division I soccer season. J Strength Cond Res 38(11): 1891-1899, 2024-Identifying physiological changes that occur in response to workload demands can help to elucidate athlete management and recovery strategies. The purpose of this study was to compare the physical and physiological demands between men and women throughout the course of a collegiate soccer season. Men ( N = 23) and women ( N = 26) soccer players participated in blood draws before preseason (T1) and every 4 weeks thereafter (T2-T4). Workload was determined at all practices and games via heart rate and global positioning satellite monitoring systems. Repeated measures multivariate analysis of variance and linear mixed models were used to assess workload and biomarker responses throughout the season ( p < 0.05). Both teams experienced the highest workloads during the first 4 weeks of the season ( p < 0.05), which was followed by several biomarker perturbations. Sex-by-Time interactions were observed for total cortisol, growth hormone, insulin-like growth factor-1, thyroxine, thyroid-stimulating hormone, vitamin D, and omega 3 fatty acid index ( p < 0.05). Additional Sex effects were observed for free and total testosterone, estrogen, prolactin, sex-hormone binding globulin, creatine kinase, and iron levels ( p < 0.05). Women soccer players experienced further Time effects for free cortisol, iron, ferritin, and percent transferrin saturation ( p < 0.05). Male soccer players experienced additional Time effects for total testosterone, estrogen, creatine kinase, interleukin-6, triiodothyronine, and ferritin ( p < 0.05). Despite similar patterns of change in workloads, differential fluctuations in physiological markers were observed between the sexes. Understanding sex differences in response to comparable workloads may enhance exercise prescriptions for better athlete management plans. Additional strategies to increase iron may be warranted in female athletes.

Phase 2b randomized clinical trial of amlitelimab, an anti-OX40 ligand antibody, in patients with moderate-to-severe atopic dermatitis

Amlitelimab, a fully human nondepleting monoclonal antibody targeting OX40 ligand on antigen-presenting cells, could prevent T-cell-driven inflammation seen in atopic dermatitis (AD). This trial evaluated the efficacy and safety of amlitelimab in adults with AD. In this 2-part, phase 2b, randomized, double-blinded placebo-controlled trial (NCT05131477), patients received subcutaneous amlitelimab every 4 weeks at doses of 250 mg with 500-mg loading dose, 250 mg, 125 mg, or 62.5 mg, or placebo for 24 weeks in Part 1 (1:1:1:1:1 randomization). In Part 2, clinical responders were reallocated 3:1 to withdraw amlitelimab or continue the previous dose regimen for 28 weeks. The primary end point was percent change in Eczema Area and Severity Index (EASI) from baseline to Week 16. 390 and 190 patients enrolled in Part 1 and Part 2, respectively. Significant percent change decreases in EASI were observed with amlitelimab vs. placebo (P<.001). Clinical responses at Week 24 (Investigator Global Assessment 0/1 and/or EASI-75) were maintained at Week 52 in patients continuing or withdrawn from amlitelimab. In patients maintaining clinical response at Week 52 while off-treatment, >80% had serum amlitelimab concentrations below a 4-μg/mL threshold for several weeks prior to Week 52. Reductions in AD-related biomarkers during Part 1 were maintained through Part 2. Amlitelimab was well tolerated over 52 weeks. Amlitelimab treatment significantly reduced clinical and biomarker responses, and was well tolerated in adults with AD through Week 52. Sustained responses were observed in the majority of patients after amlitelimab withdrawal for 28 weeks.

Integrated single-cell transcriptome and TCR profiles of hepatocellular carcinoma highlight the convergence on interferon signaling during immunotherapy

BackgroundDespite the success of immune checkpoint inhibitor (ICI)-based combination therapies in hepatocellular carcinoma (HCC), its effectiveness remains confined to a subset of patients. The development of reliable, predictive markers is...

Phytomonitoring of Air Pollution Around Brick Kilns in Urban Area: Exploring the Potential of Plants for the Remediation of Pollutants

This study examines the impacts of various pollutants on foliar biochemical parameters, including relative water content (RWC), total chlorophyll, leaf extract pH, and ascorbic acid content, and their relationship with the Air Pollution Tolerance Index (APTI). RWC, a crucial indicator of plant resilience, showed a significant positive correlation with APTI values (r = 0.4503, p < 0.05). Species with higher RWC, such as Carica papaya and Cassia fistula, demonstrated enhanced tolerance to pollutants, with RWC values reaching up to 85%. Chlorophyll content, which is vital for photosynthesis, exhibited a significant reduction in polluted areas, with levels ranging from 0.28 to 3.23 mg/g (p < 0.05). Notably, Cassia fistula had high APTI values but lower chlorophyll content, reflecting the complex relationship between tolerance and chlorophyll levels. Leaf extract pH was significantly lower in polluted areas, with pH values consistently below 7, correlating with higher APTI values (p < 0.05). Ascorbic acid content, an important antioxidant, was significantly higher in plants exposed to pollution, with positive correlations to APTI (r = 0.9214) and pH levels (r = 0.62). Principal Component Analysis (PCA) identified that pH, ascorbic acid, and APTI were positively correlated, while total chlorophyll and RWC showed opposing trends. Sensitivity analysis indicated that RWC (95.84% impact on Carica papaya and 85.92% on Cassia fistula) and pH were the primary factors influencing APTI and Metal Accumulation Index (MAI) values. The findings underscore the role of RWC, chlorophyll, pH, and ascorbic acid as biomarkers for plant responses to pollution and highlight the effectiveness of species with high MAI values in heavy metal accumulation and environmental monitoring.

Repair-assisted damage detection as a potential predictive biomarker for immunotherapy response in ovarian cancer

Repair-assisted damage detection as a potential predictive biomarker for immunotherapy response in ovarian cancer

Dynamic Anthropometrics in Pancreatic Cancer: Associations Between Body Composition Changes During Neoadjuvant Therapy and Survival Outcomes After Resection.

Assessment of individual tumor biology and response to systemic therapy in pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge. The significance of anthropometric (body composition) changes during chemotherapy as a surrogate for tumor biology in the setting of localized PDAC is unknown. A retrospective, single-institution analysis of patients with PDAC who received neoadjuvant therapy (NAT) and pancreatectomy from 2017 to 2021 was performed. Radiologic anthropometric analysis used artificial intelligence-driven software to segment and compute total and sub-compartment muscle area, adipose tissue area, and attenuation values at the level of the L3 vertebra. Kaplan-Meier survival estimates, log-rank tests, and multivariable Cox regression models were used in survival analyses. The inclusion criteria were met by 138 patients. Although decreases in muscle and adipose tissue areas during NAT were predominant, a subset of patients experienced an increase in these compartments. Increases in muscle greater than 5% (hazard ratio [HR], 0.352; 95% confidence interval [CI] 0.135-0.918; p=0.033) and increases in adipose tissue greater than 15% (HR, 0.375; 95% CI 0.144-0.978; p=0.045), were significantly associated with improved survival, whereas loss of visceral fat greater than 15% was detrimental (HR 1.853; CI 1.099-3.124; p=0.021). No significant associations with single time-point anthropometrics were observed. Gains in total muscle and adipose mass were associated with improved pathologic response to systemic therapy and less advanced pathologic tumor stage. Dynamic anthropometric analysis during NAT for PDAC is a stronger prognostic indicator than measurements taken at a single point in time. Repeated anthropometric analysis during preoperative chemotherapy may serve as a biomarker for individual tumor biology and response to therapy.