Predictive Value For Response Research Articles

Comprehensive Analysis Reveals That ISCA1 Is Correlated with Ferroptosis-Related Genes Across Cancers and Is a Biomarker in Thyroid Carcinoma

Background: ISCA1 (Iron–Sulfur Cluster Assembly 1) is involved in the assembly of iron–sulfur (Fe–S) clusters, which are vital for electron transport and enzyme activity. Some studies suggest the potential involvement of ISCA1 in tumor progression through interactions with ferroptosis-related genes (FRGs) and the tumor immune microenvironment (TME). However, there has been no systematic analysis of its role in FRGs and the TME or its predictive value for prognosis and immunotherapy response across different cancer types. Methods: In this study, we analyzed the expression and prognosis of ISCA1 RNA, CNV, methylation, and protein in multiple tumor tissues via data from the TCGA and CPTAC databases and clinical information. We conducted a comprehensive analysis of the correlations between ISCA1 and FRGs, immune-related genes (including immune regulatory genes and immune checkpoint genes), immune cell infiltration, immune infiltration scores, tumor stemness, and genomic heterogeneity. Results: We performed drug prediction and validation through molecular docking and molecular dynamics analysis to identify candidate drugs that could promote or inhibit ISCA1 RNA expression. Our findings revealed that ISCA1 could serve as a biomarker in thyroid carcinoma, play a role with different FRGs in various cell types, and mediate different ligand–receptor pathways for cell–cell communication. Conclusions: Overall, our study highlights the potential of ISCA1 as a novel biomarker for predicting prognosis and immunotherapeutic efficacy in thyroid carcinoma and suggests its potential for developing novel antitumor drugs or improving immunotherapy.

Can Circulating Tumor DNA Improve the Predictive Value of Interim Response in Patients with Advanced Hodgkin Lymphoma and PET-2 DS3?

Background: Analysis of 441 patients with classical HL in advanced stages from the Czech Hodgkin Lymphoma Registry treated with 6 or 4 cycles of eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) according to the interim PET-2 has shown that within patients that received 4 cycles of eBEACOPP, there is a trend for a higher 5-year progression-free survival (PFS) in patients with PET-2 Deauville score (DS) 1-2 in comparison to patients with PET-2 DS3 (91% [95% CI 84-99] vs. 78% [95% CI 64-95], p=0.061), accepted for ISHL13. To better stratify patients with PET-2 DS3 into 4 or 6 cycles of eBEACOPP, we analyzed circulating tumor DNA (ctDNA) within the ongoing trial NCT06263530 and correlated it with interim PET-2 results. Methods: To analyze ctDNA levels and its dynamics, we collected peripheral blood from 67 patients with classical HL in advanced stages III/IV, including clinical stages IIB with massive mediastinal tumor and/or extranodal involvement. 60 patients received eBEACOPP (30 patients 4 cycles and 30 patients 6 cycles), 4 patients received combination of eBEACOPP (4 cycles) and ABVD (2 cycles), and only 3 patients received 6 cycles of ABVD. Blood samples were collected at diagnosis, after two cycles of chemotherapy, and at the end of treatment (EoT). Following cell free DNA extraction, levels of ctDNA were determined using a custom panel of 538 genes frequently altered in lymphomas utilizing next generation sequencing-based CAPP-Seq (CAncer Personalized Profiling by deep Sequencing) approach. Plasma ctDNA levels were consequently correlated with PET results at the same timepoints. Results: Out of 67 patients (all white race, male gender 39 patients, median age at diagnosis 33 with range 19 - 70 years) 56 achieved PET-2 metabolic complete remission - CMR (30 patients DS1-2 and 26 patients DS3) and 11 patients achieved partial remission - PR (DS4-5). At the end of chemotherapy, the number of CMR increased to 61, 5 patients were in PR, and unknown response was achieved in 1 patient. Overall, 9 patients relapsed/progressed after the first-line treatment (with interim PET-2: DS2 in 3 patients, DS3 in 2 patients, and DS4-5 in 4 patients). Preliminary analysis suggests that ctDNA might improve PET-2 based disease status evaluation and patient stratification. Correlation of ctDNA with interim PET-2 and EoT PET will be presented. Conclusion: ctDNA is a promising sensitive tool to better stratify treatment of patients with Hodgkin lymphoma. This work was supported by grants AZV NU22-03-00182 from the Ministry of Health of the Czech Republic, MH CZ DRO (FNOl_00098892, VFN00064165), National Institute for Cancer Research (EXCELES - LX22NPO5102), Cooperatio Program (research areas Oncology and Haematology and Biology), and SVV 260637.

Long-term outcomes among patients who respond within the first year to nivolumab plus ipilimumab or nivolumab monotherapy: A pooled analysis in 935 patients

PurposeTo investigate the predictive value of RECIST response within 3, 6, or 12 months on long-term survival, and explore differences between nivolumab+ipilimumab and nivolumab monotherapy, we analyzed pooled 5-year data of 935 responder and non-responder patients at various time points after treatment initiation in CheckMate 069, 066, and 067 studies. Patients and methodsTreatment-naive advanced melanoma patients received nivolumab+ipilimumab or nivolumab monotherapy. To decrease immortal time bias, 3-, 6-, or 12-month overall survival (OS) and progression-free survival (PFS) landmark analyses were performed. Association between characteristics and response was evaluated by univariate and multivariate analyses. ResultsResponse rates at any time were 58 % (239/409) for nivolumab+ipilimumab and 44 % (230/526) for nivolumab monotherapy. In 12-month landmark analyses, 5-year OS rates for responders versus non-responders were 82 % versus 40 % with nivolumab+ipilimumab (HR=0.23 [95 % CI, 0.15–0.35]) and 76 % versus 32 % with nivolumab monotherapy (HR=0.22 [95 % CI, 0.16–0.31]). PFS rates were 83 % versus 32 % and 69 % versus 46 %, respectively. Similar strong associations between response at 3 and 6 months and 5-year OS and PFS were also observed with more than 70 % of the responses observed in the first 3 months. Response rates correlated with baseline LDH and PD-L1 status by multivariate analysis but the association between response and long-term survival was maintained in landmark analyses even among patients with high LDH and low PD-L1 expression. ConclusionClinical response evaluated in the first months of therapy is a strong predictor of long-term survival, even in patients with poor prognostic biomarkers.

Dewatering and drying of Kombucha Bacterial Cellulose for preparation of biodegradable film for food packaging

Kombucha Bacterial Cellulose (KBC), obtained from waste products of kombucha fermentation, has potential applications in diverse fields. The present study used tea waste as a raw material for producing kombucha-like beverages and bacterial cellulose (BC). The in-situ dewatering and drying operations were performed to remove the high-water content from fermented KBC. Herein, the performance of BC in pressure-driven separation has been investigated as a function of dewatering pressure, drying temperature, and drying time in a multifunctional filtration cell. The Central Composite Design (CCD) was used to optimize the dewatering and drying parameters. The optimum conditions were found to be 4 bar pressure, 99 °C drying temperature, and 5 min drying time with a desirability value of 0.921. The predicted response values agreed with actual responses within 2.3–2.7 %. The dried films were prepared at optimized conditions and used to investigate thickness, density, mechanical properties, Fourier transform infrared, and scanning electron microscopy. The properties of KBC film varied as fermentation days increased. The KBC films' transparency decreased as thickness and density increased. The KBC film exhibits excellent mechanical properties such as tensile strength, maximum load, extension at the break, load at the break, and Young's modulus. The KBC films have been reported to be biodegradable and non-toxic and may be used for food packaging. Moreover, the present study successfully demonstrated that KBC packaging material could extend the shelf life of tomatoes by 13–15 days under accelerated conditions.

A flattening systolic blood pressure response at the end of ramp exercise testing is not associated with all-cause mortality

Abstract Purpose Systolic blood pressure (SBP) is expected to rise linearly during ramp exercise, but sometimes plateaus before the end of exercise. We aimed to examine the predictive value of a plateauing SBP response at the end of a cycle exercise test. Methods We analyzed 9,001 consecutive patients aged ≥18 years with maximal cycle ergometer ramp tests, after excluding subjects with valvulopathy, pacemaker, arrhythmia during the test, or body mass index (BMI) >40kg/m², as well as tests with resting SBP <80mmHg or >200mmHg, exercise SBP <100 mmHg, <2 SBP measurements during the second half of the test or a test duration <4 minutes. The data were cross-linked with nationwide registries for mortality and in- and outpatient hospital diagnoses. The difference in SBP between the two last SBP measurements was standardized to the difference in Watts between the same time points, categorized as i) an SBP decrease (drop), ii) an SBP increase of <2.5 mmHg per 10 Watts increase (flat), iii) an SBP increase of 2.5-15 mmHg/10 Watts (intermediate), and iv) an SBP increase >15 mmHg/10 Watts representing the 97.5th percentile (steep). Hazards ratios (HR, [95% confidence interval, CI]) for all-cause mortality were calculated, stratified for exercise capacity (peak Watt % of predicted) with the intermediate SBP response as reference. Adjustments were made for age, sex, BMI, resting SBP, baseline diagnosis of ischemic heart disease, heart failure, chronic obstructive pulmonary disease, and the use of beta-blockers or anti-hypertensive medication. Results Decreasing, flat, intermediate, and steep SBP responses at the end of exercise were present in 1.1%, 25.6%, 70.8% and 2.5% of patients respectively (Table 1). During median follow-up 8.6 years (interquartile range 5.9–11.6 years) there were 844 deaths. When compared to an intermediate SBP response, a flat SBP response was not associated with all-cause mortality in any of the exercise capacity strata: lowest tertile of Wmax%pred unadjusted HR 0.88 (95% CI 0.69–1.11), middle tertile HR 0.91 (95% CI 0.66–1.24), and highest tertile HR 0.95 (95% CI 0.64–1.41), with HRs remaining non-significant after adjustment for covariates (Table 2). Conclusion In patients referred for exercise testing, a flattening SBP response at the end of exercise was not associated with increased all-cause mortality risk compared to an intermediate SBP response, consistent across the different exercise capacity strata.

Halving Time of BCR-ABL Transcripts as a Precise Predictor for Deep Molecular Response in Patients with Chronic Myeloid Leukemia Treated with TKI

To investigate the early predictive value of halving time (HT) of BCR-ABLIS for deep molecular response (DMR) in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitor (TKI). The continuous data of newly diagnosed CML patients with complete case data and first-line imatinib treatment admitted to the Affiliated Hospital of Inner Mongolia Medical University from January 2014 to June 2022 were retrospectively analyzed. Combined with the clinical characteristics of the patients and the efficacy analysis at each time point, a logistic regression model was used to explore the independent influencing factors of DMR, and combined HT of BCR-ABLIS with BCR-ABLIS level at 3 months to predict DMR of the patients. Univariate and multivariate analyses showed that HT and 3-month BCR-ABLIS levels were independent influencing factors for MR4, MR4.5, and stable MR4.5 ( P < 0.05). ROC curve analysis determined that the best cut-off value of HT was 28 days. Compared with patients with HT>28 d, patients with HT≤28 d were more likely to obtain DMR at 2, 3, and 5 years, respectively (74.2% vs 27.3%, 71.2% vs 22.7%, and 63.6% vs 25.0%, all P < 0.001). The patients were divided into 4 groups according to BCR-ABLIS levels at 3 months and HT. Kaplan-Meier analysis showed that the patients in the BCR-ABLIS≤10% and HT≤28 d group had a higher probability of obtaining cumulative MR4 and MR4.5 than those in the BCR-ABLIS≤10% and HT>28 d group (P < ＜0.05); Patients in the BCR-ABLIS>10% and HT≤28 d group had a higher probability of obtaining cumulative MR4 and MR4.5 than those in the BCR-ABLIS＞10% and HT>28 d group ( P < 0.05). In addition to BCR-ABLIS level, HT of BCR-ABLIS can be used as another important predictor of treatment efficacy in CML patients. The combination of BCR-ABLIS level and HT has a more accurate predictive value for long-term molecular response of CML patients after TKI treatment.

Evaluating the feasibility and predictive accuracy of biodynamic imaging to platinum-based chemotherapy response in esophageal adenocarcinoma.

Esophageal cancer management lacks reliable response predictors to chemotherapy. In this study we evaluated the feasibility and accuracy of Biodynamic Imaging (BDI), a technology that employs digital holography as a rapid predictor of chemotherapy sensitivity in locoregional esophageal adenocarcinoma. Pre-treatment endoscopic pinch biopsies were collected from patients with esophageal adenocarcinoma during standard staging procedures. BDI analyzed the tumor samples and assessed in vitro chemotherapy sensitivity. BDI sensitivity predictions were compared to patients' pathological responses, the gold standard for determining clinical response, in the surgically treated subset (n=18). BDI was feasible with timely tissue acquisition, collection, and processing in all 30 enrolled patients and successful BDI analysis in 28/29 (96%) eligible. BDI accurately predicted chemotherapy response in 13/18 (72.2%) patients using a classifier for complete, marked, and partial/no-response. BDI technology had 100% negative predictive value for complete pathological response hence identifying patients unlikely to respond to treatment. BDI technology can potentially predict patients' response to platinum chemotherapy. Additionally, this technology represents a promising step towards optimizing treatment strategies for esophageal adenocarcinoma patients by pre-emptively identifying non-responders to conventional platinum-based chemotherapy.

Evaluation of serum fibronectin levels and fibronectin gene polymorphism in patients receiving intravesical BCG therapy for non-muscle invasive bladder cancer and its prognostic value

BackgroundBladder cancer continues to be a significant health issue, leading to ongoing research into novel biomarkers and treatment strategies. This study aims to evaluate the potential of serum fibronectin levels and fibronectin gene polymorphisms as biomarkers for predicting the recurrence and treatment response in patients with NMIBC undergoing intravesical BCG therapy.MethodsBetween June 2022 and December 2022, data of 73 patients who applied to the Mersin University Urology Clinic due to NMIBC and were followed and treated in our clinic, receiving intravesical BCG treatment, when necessary, as well as 56 individuals without any malignancy, were prospectively examined. Serum fibronectin levels were measured using the enzyme-linked immunosorbent assay method. PCR testing was applied for the fibronectin gene RS10202709 and RS 35,343,655 gene polymorphisms by using Real-Time PCR.ResultsThe mean serum fibronectin level in the patient group was 76.794 ± 66.998ng/ml. Simultaneously, it was 50.486 ± 25.156ng/ml in the control group, and these differences in serum fibronectin levels were statistically significant(p = 0.003). Out of the 73 patients included in the study, recurrence of bladder cancer was observed in 53 of them. They were divided into two groups based on the recurrence times: early recurrence and late recurrence. The mean fibronectin level in the early recurrence group was 102 ± 86.1 ng/ml, while it was 44.7 ± 11.8 ng/ml in the late recurrence group. Emphasize the significance of the higher fibronectin levels in the early recurrence group by stating, patients with early recurrence exhibited significantly higher serum fibronectin levels compared to those with late recurrence (p < 0.001), suggesting a potential role for fibronectin as a prognostic biomarker.ConclusionsThe statistically higher concentrations of serum fibronectin levels in patients with bladder cancer observed in our study are a noteworthy finding. These findings suggest that serum fibronectin levels could serve as a valuable prognostic biomarker for early recurrence in NMIBC patients, although their predictive value for BCG treatment response remains limited.

Optimization of Motor Rotor Punch Wear Parameters Based on Response Surface Method

To reduce the wear of the motor rotor punching punch and ensure the efficiency is the highest in actual production, the finite element analysis software Deform-3Dv11 is used to simulate the punch wear based on the Archard model theory. With punch wear as the response target and punch speed, punch clearance, and punch edge fillet as the main factors, 17 groups of response surface Box–Behnken test designs are established, as well as a quadratic polynomial regression model between the main factors and the response. The results revealed that: the influence of various parameters on punch wear is in the order of punch edge fillet C &gt; punch clearance B &gt; punch speed A; the order of the interactive influence of various factors is as follows: punch speed and punch edge fillet AC &gt; punch speed and punch clearance AB &gt; punch clearance and punch edge fillet BC. The optimal blanking process combination obtained by using Design-Expert13 software is as follows: blanking speed 50 mm/s, blanking clearance 0.036 mm, and die cutting edge rounded corner 0.076 mm; the predicted response surface value is 6.95 × 10−12 mm. Through simulation verification, the actual optimized simulation value is 6.93 × 10−12 mm, with an absolute relative error of 2.5% for the predicted response value. Moreover, the optimized simulation value is reduced by 30.4% compared to the one before optimization, effectively reducing the punch wear of the motor rotor punching forming and providing a theoretical foundation for further wear optimization.

Candidate Biomarkers for Response to Treatment in Psoriatic Disease.

To determine whether biologic therapy alters serum C-X-C motif chemokine ligand 10 (CXCL10), matrix metalloproteinase 3 (MMP3), S100 calcium-binding protein A8 (S100A8), acid phosphatase 5 (ACP5), and C-C motif chemokine ligand 2 (CCL2) levels in patients with psoriatic arthritis (PsA) and cutaneous psoriasis without arthritis (PsC), and whether baseline levels of these proteins predict response to treatment for PsA. We included (1) patients with PsA taking tumor necrosis factor inhibitors (TNFi), interleukin 17 inhibitors (IL-17i), methotrexate (MTX), and those who were untreated with bDMARDs or csDMARDs; (2) patients with PsC taking bDMARDs; and (3) matched patients with PsC who were not treated with bDMARDs or csDMARDs. Serum samples at baseline and at the 3- to 6-month follow-up visit were retrieved from the biobank. Protein levels were quantified using a Luminex multiplex assay. We compared follow-up vs baseline protein levels within groups and change in levels between groups. For the predictive potential of the biomarkers, we developed logistic regression classification models. Response to treatment was defined as (1) achieving low disease activity or remission (according to the Disease Activity Index for Psoriatic Arthritis); (2) ≥ 75% reduction in Psoriasis Area and Severity Index; and (3) ≥ 50% reduction in actively inflamed joint count. In PsA, TNFi reduced serum levels of all 5 proteins, IL-17i increased ACP5 and CCL2, and MTX reduced MMP3. Changes in MMP3 and S100A8 levels were significantly different between untreated PsA and matched biologic-treated PsA (P < 0.05). There were no significant differences between treated or untreated patients with PsC. Baseline levels of CXCL10, MMP3, S100A8, and ACP5 had good predictive value (area under the curve > 0.80) for response to biologics in patients with PsA. Treatment with biologics and MTX affect serum CXCL10, MMP3, S100A8, ACP5, and CCL2 levels in patients with PsA. MMP3, S100A8, ACP5, and CXCL10 have potential use as serum biomarkers to predict response to treatment for PsA.

Predictive potential of dynamic contrast-enhanced MRI and plasma-derived angiogenic factors for response to concurrent chemoradiotherapy in human papillomavirus-negative oropharyngeal cancer.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascularity, which depends on the process of angiogenesis and affects tumour response to treatment. Our study explored the associations between DCE-MRI parameters and the expression of plasma angiogenic factors in human papilloma virus (HPV)-negative oropharyngeal cancer, as well as their predictive value for response to concurrent chemoradiotherapy (cCRT). Twenty-five patients with locally advanced HPV-negative oropharyngeal carcinoma were prospectively enrolled in the study. DCE-MRI and blood plasma sampling were conducted before cCRT, after receiving a radiation dose of 20 Gy, and after the completion of cCRT. Perfusion parameters ktrans, kep, Ve, initial area under the curve (iAUC) and plasma expression levels of angiogenic factors (vascular endothelial growth factor [VEGF], connective tissue growth factor [CTGF], platelet-derived growth factor [PDGF]-AB, angiogenin [ANG], endostatin [END] and thrombospondin-1 [THBS1]) were measured at each time-point. Patients were stratified into responders and non-responders based on clinical evaluation. Differences and correlations between measures were used to generate prognostic models for response prediction. Higher perfusion parameter ktrans and higher plasma VEGF levels successfully discriminated responders from non-responders across all measured time-points, whereas higher iAUC and higher plasma PDGF-AB levels were also discriminative at selected time points. Using early intra-treatment measurements of ktrans and VEGF, a predictive model was created with cut-off values of 0.259 min-1 for ktrans and 62.5 pg/mL for plasma VEGF. Early intra-treatment DCE-MRI parameter ktrans and plasma VEGF levels may be valuable early predictors of response to cCRT in HPV-negative oropharyngeal cancer.

BCAM (basal cell adhesion molecule) protein expression in different tumor populations

Basal Cell Adhesion Molecule (BCAM), a receptor for laminin subunit α5, plays a crucial role in the pathogenesis of various malignancies. Notably, evidence of hypermethylation at multiple immune checkpoints in patients with low BCAM expression suggests these individuals may respond favorably to immunotherapy using ICIs (immune checkpoint inhibitors). This finding lays the foundation for the hypothesis that BCAM may serve as an important biomarker in cancer patients. To investigate this potential, we evaluated BCAM expression patterns in 3114 patients from both discovery and validation cohorts, spanning seven cancer types, using quantitative immunofluorescence (QIF). We also explored the correlation between BCAM and PD-L1 expressions within these cohorts, aiming to establish its potential predictive value for immunotherapy response. Our findings indicate that BCAM was highly expressed in ovarian (79.2%) and lung (78.5%) tumors, with lower yet significant expression in breast (37.7%), head and neck (31.3%), and bladder-urothelial tumors (27.6%). Notably, high BCAM expression was associated with better OS in NSCLC. More importantly, BCAM expression did not correlate with PD-L1 protein expression in any of these tumors, highlighting its independent predictive potential. The widespread expression of BCAM across multiple tumor types, coupled with its lack of correlation with PD-L1 expression, highlights its potential as a predictive novel biomarker across various cancer types.

Identification of DNA methylation-regulated WEE1 with potential implications in prognosis and immunotherapy for low-grade glioma.

WEE1 is a critical kinase in the DNA damage response pathway and has been shown to be effective in treating serous uterine cancer. However, its role in gliomas, specifically low-grade glioma (LGG), remains unclear. The impact of DNA methylation on WEE1 expression and its correlation with the immune landscape in gliomas also need further investigation. This study used data from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) and utilized various bioinformatics tools to analyze gene expression, survival, gene correlation, immune score, immune infiltration, genomic alterations, tumor mutation burden, microsatellite instability, clinical characteristics of glioma patients, WEE1 DNA methylation, prognostic analysis, single-cell gene expression distribution in glioma tissue samples, and immunotherapy response prediction based on WEE1 expression. WEE1 was upregulated in LGG and glioblastoma (GBM), but it had a more significant prognostic impact in LGG compared to other cancers. High WEE1 expression was associated with poorer prognosis in LGG, particularly when combined with wild-type IDH. The WEE1 inhibitor MK-1775 effectively inhibited the proliferation and migration of LGG cell lines, which were more sensitive to WEE1 inhibition. DNA methylation negatively regulated WEE1, and high DNA hypermethylation of WEE1 was associated with better prognosis in LGG than in GBM. Combining WEE1 inhibition and DNA methyltransferase inhibition showed a synergistic effect. Additionally, downregulation of WEE1 had favorable predictive value in immunotherapy response. Co-expression network analysis identified key genes involved in WEE1-mediated regulation of immune landscape, differentiation, and metastasis in LGG. Our study shows that WEE1 is a promising indicator for targeted therapy and prognosis evaluation. Notably, significant differences were observed in the role of WEE1 between LGG and GBM. Further investigation into WEE1 inhibition, either in combination with DNA methyltransferase inhibition or immunotherapy, is warranted in the context of LGG.

Identification of a Novel Activated NK-Associated Gene Score Associated with Diagnosis and Biological Therapy Response in Ulcerative Colitis

Introduction: Natural killer (NK) cells are associated with the pathogenesis of ulcerative colitis (UC); however, their precise contributions remain unclear. The present study aimed to investigate the diagnostic value of the activated NK-associated gene (ANAG) score in UC and evaluate its predictive value in response to biological therapy. Methods: Bulk RNA-seq and scRNA-seq datasets were obtained from the Gene Expression Omnibus (GEO) and Single Cell Portal (SCP) databases. In the bulk RNA-seq, differentially expressed genes (DEGs) were screened by the “Batch correction” and “Robust rank aggregation” (RRA) methods. The immune infiltration landscape was estimated using single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT. DEGs that correlated with activated NK cells were identified as activated NK-associated genes (ANAGs). Protein-protein interaction (PPI) analysis and least absolute shrinkage and selection operator (LASSO) regression were used to screen key ANAGs and establish an ANAG score. The expression levels of the four key ANAGs were validated in human samples by real-time quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence. The potential therapeutic drugs for UC were identified using the DSigDB database. Through scRNA-seq data analysis, the cell scores based on the ANAGs were calculated by “AddModuleScore” and “AUCell.” Results: Immune infiltration analysis revealed a higher abundance of activated NK cells in noninflamed UC tissues (ssGSEA, p < 0.001; CIBERSORT, p < 0.01). Fifty-four DEGs correlated with activated NK cells were identified as ANAGs. The ANAG score was established using four key ANAGs (SELP, TIMP1, MMP7, and ABCG2). The ANAG scores were significantly higher in inflamed tissues (p < 0.001) and in biological therapy nonresponders (NR) tissues before treatment (golimumab, p < 0.05; ustekinumab, p < 0.001). The ANAG score demonstrated an excellent diagnostic value (AUC = 0.979). Patients with higher ANAG scores before treatment were more likely to experience a lack of response to golimumab or ustekinumab (golimumab, p < 0.05; ustekinumab, p < 0.001). Conclusion: This study established a novel ANAG score with the ability to precisely diagnose UC and distinguish the efficacy of biological treatment.

Correlation and predictive value of pathological complete response and ultrasound characteristic parameters in neoadjuvant chemotherapy for breast.

Breast cancer ranks as one of the most prevalent malignant tumors among women, significantly endangering their health and lives. While radical surgery has been a pivotal method for halting disease progression, it alone is insufficient for enhancing the quality of life for patients. To investigate the correlation between ultrasound characteristic parameters of breast cancer lesions and clinical efficacy in patients undergoing neoadjuvant chemotherapy (NAC). Employing a case-control study design, this research involved 178 breast cancer patients treated with NAC at our hospital from July 2019 to June 2022. According to the Miller-Payne grading system, the pathological response, i.e. efficacy, of the NAC in the initial breast lesion after NAC was evaluated. Of these, 59 patients achieved a pathological complete response (PCR), while 119 did not (non-PCR group). Ultrasound characteristics prior to NAC were compared between these groups, and the association of various factors with NAC efficacy was analyzed using univariate and multivariate approaches. In the PCR group, the incidence of posterior echo attenuation, lesion diameter ≥ 2.0 cm, and Alder blood flow grade ≥ II were significantly lower compared to the non-PCR group (P < 0.05). The area under the curve values for predicting NAC efficacy using posterior echo attenuation, lesion diameter, and Alder grade were 0.604, 0.603, and 0.583, respectively. Also, rates of pathological stage II, lymph node metastasis, vascular invasion, and positive Ki-67 expression were significantly lower in the PCR group (P < 0.05). Logistic regression analysis identified posterior echo attenuation, lesion diameter ≥ 2.0 cm, Alder blood flow grade ≥ II, pathological stage III, vascular invasion, and positive Ki-67 expression as independent predictors of poor response to NAC in breast cancer patients (P < 0.05). While ultrasound characteristics such as posterior echo attenuation, lesion diameter ≥ 2.0 cm, and Alder blood flow grade ≥ II exhibit limited predictive value for NAC efficacy, they are significantly associated with poor response to NAC in breast cancer patients.

On sensitivity analysis of the fundamental frequency of cracked fiber metal laminated (FML) beams using experimental survey and finite element method

PurposeIn this research, the free vibration sensitivity analysis of cracked fiber metal laminated (FML) beams is investigated numerically and experimentally. The effects of single and double cracks on the frequency of the cantilever beams are simulated using the finite element method (FEM) and compared to the experimental results.Design/methodology/approachIn FEM analysis, the crack defect is simulated by the contour integral technique without considering the crack growth. The specimens are fabricated with an aluminum sheet, woven carbon fiber and epoxy resin. The FML specimens are constructed by bonding five layers as [carbon fiber-epoxy/Al/carbon fiber-epoxy/Al/carbon fiber-epoxy]. First, the location and length of cracks are considered input factors for the frequency sensitivity analysis. Then, the design of the experiment is produced in the cases of single and double cracks to compute the frequency of the beams in the first and second modes using the FEM. The mechanical shaker is used to determine the natural frequency of the specimens. In addition, the predicted response values of the frequency for the beam are used to compare with the experimental results.FindingsConsequently, the results of the sensitivity analysis demonstrate that the location and length of the crack have significant effects on the modes.Originality/valueEffective interaction diagrams are introduced to investigate crack detection for input factors, including the location and length of cracks in the cases of single and double cracks.

26 Applying single cell RNA sequencing of sarcomatoid renal cell carcinoma for the development of a novel transcriptomic biomarker to predict immunotherapy response

Abstract Background Renal cell carcinoma with sarcomatoid features (sRCC) is a unique kidney cancer subtype associated with aggressive biology and poor clinical outcomes. Intriguingly, sRCC has recently exhibited preferential responsiveness to immune checkpoint blockade (ICB) therapies. Within the RCC population, however, there currently is a paucity of biomarkers predictive for ICB response, representing a critical unmet clinical need for optimal therapy selection. Therefore, we sought to derive a transcriptomic signature from sRCC samples encapsulating this paradoxical hyper-aggression and ICB-responsiveness to identify RCC patients most likely to benefit from ICB irrespective of sarcomatoid feature presence. Methods Nephrectomy specimens from patients with RCC were processed for single cell RNA sequencing (scRNAseq). Clustering was performed and annotated tumor cells were computationally isolated. Tumor cell counts were aggregated and differential expression between sRCC and non-sRCC cases was performed. Genes significantly upregulated in sRCC were next filtered against differential gene expression data of sRCC vs non-sRCC from three clinical RCC datasets (TCGA, CheckMate, &amp; Javelin101) to identify genes enriched in sRCC across scRNAseq and bulk RNA sequencing. The prognostic and predictive features of this gene signature were then assessed in cohorts of patients with RCC receiving ICB. Results In total, 73,123 unique cells from 18 RCC patients (10 sRCC; 8 clear cell RCC) were analyzed by scRNAseq, including 5,386 tumor cells. Differential gene expression of tumor clones revealed 20 genes significantly enriched in sRCC relative to ccRCC. Filtering against public differential gene expression data resulted in 10 genes included within the final Sarcomatoid Signature (SS). SS expression scores for clinical specimens were calculated by single-sample gene set enrichment analysis. SS scores were significantly enriched in sRCC patient tumors across TCGA KIRC, CheckMate, and IMmotion151 datasets (p&amp;lt;0.001 for all cohorts). Within TCGA KIRC, SS scores were significantly increased in patients with nuclear grade 4 (p&amp;lt;0.001) and metastatic (p&amp;lt;0.001) disease, while stratification by median SS score revealed worsened overall (HR=2.19, p&amp;lt;0.001) and disease-free (HR=2.08, p&amp;lt;0.001) survival among SS-high patients. Amongst the CheckMate cohort (including patient samples from the CheckMate-010 &amp; CheckMate-025 trials), SS-high patients experienced improved progression free survival (PFS) when treated with nivolumab relative to everolimus (HR=0.70, p=0.055), whereas no difference was seen between therapies in the SS-low patient population (HR=0.98, p=0.9). In the IMmotion151 trial, which was not utilized for gene filtering and signature refinement and thus represents an independent validation cohort, SS-high patients experienced reduced PFS duration (HR=1.39, p&amp;lt;0.001) irrespective of treatment arm. However, SS-high patients experienced improved objective response rates with the ICB-containing atezolizumab/bevacizumab regimen compared to sunitinib (p&amp;lt;0.001) and relative to SS-low patients receiving atezolizumab/bevacizumab (p=0.028) (Figure 1). Within the SS-high population, patients experienced prolonged PFS with atezolizumab/bevacizumab (HR=0.70, p=0.003) relative to sunitinib whereas no PFS difference between arms was seen in the SS-low population (HR=1.01, p&amp;gt;0.99). Conclusions This novel SS derived from scRNAseq demonstrates negative prognostic yet positive predictive value for ICB response. In a domain currently void of efficacious biomarkers, the SS, upon prospective validation, may assist in optimal therapy selection for patients with RCC.

Long-term effect of obstructive sleep apnoea management on blood pressure in patients with resistant hypertension: the SARAH study.

There is a close relationship between obstructive sleep apnoea (OSA) and resistant hypertension (RH). However, studies assessing the long-term effect of diagnosing and treating OSA on blood pressure (BP) control in these patients are lacking. To address this gap, we recruited 478 RH patients from hypertension units and followed them prospectively after they were screened for OSA through a sleep study. By performing 24-h ambulatory BP monitoring (ABPM) annually, the effect of OSA management was assessed. The patients had a median (interquartile range (IQR)) age of 64.0 (57.2-69.0) years, 67% were males and most were nonsleepy, with a median (IQR) apnoea-hypopnoea index (AHI) of 15.8 (7.9-30.7) events·h-1. The median (IQR) follow-up time was 3.01 (2.93-3.12) years. At baseline, severe OSA was associated with uncontrolled BP, nocturnal hypertension and a nondipper circadian BP pattern. Moreover, these patients had higher BP values during follow-up than did patients in the other groups. However, among patients with moderate and severe OSA, the management of sleep disordered breathing, including the implementation of continuous positive airway pressure treatment, was associated with a reduction in 24-h ABPM parameters, especially night-time BP values, at the 1-year follow-up. These benefits were attenuated over time and only subjects with severe OSA maintained an ABPM night-time reduction at 3 years. Furthermore, clinical variables such as uncontrolled BP, sex and age showed a predictive value for the BP response at 1 year of follow-up. A favourable long-term decrease in BP was detected by diagnosing and treating OSA in a cohort of RH patients from hypertension units, but over time this decrease was only partially maintained in severe OSA patients.

Single-cell analysis identified PDIA3 as regulator of malignant characteristics and macrophage function in human cancers.

Protein disulfide isomerase A3 (PDIA3) is an endoplasmic reticulum (ER) protein. It has different functions including glycoprotein folding in the ER. The unfavorable prognosis of cancer patients was related to the abnormal PDIA3 expression level. However, it is unclear how PDIA3 correlates with the malignant characteristics of different tumors and its impact on tumor immunity. Pan-cancer data were downloaded from several databases for large-scale bioinformatics analysis. The immunological functions of PDIA3 were systematically explored at the single-cell sequencing level, including cell communication, cell metabolism, cell evolution and epigenetic modification. We performed immunofluorescence staining to visualize PDIA3 expression and infiltration of macrophages in pan-cancer samples. Further, we performed a loss-of-function assay of PDIA3 in vitro. The CCK8 assay, clone formation assay, and transwell assay were performed. M2 macrophages were co-cultured with different cell lines before the transwell assay was performed. The immunofluorescence staining of pan-cancer samples presented a higher expression of PDIA3 than those of the paired normal tissues. According to single-cell sequencing analysis, expression of PDIA3 was closely associated with cell communication, cell metabolism, cell evolution and epigenetic modification. The knockdown of PDIA3 in tumor cells inhibited cell proliferation and invasion, and restrained cocultured M2 macrophage migration. Furthermore, PDIA3 displayed predictive value in immunotherapy response in human cancer cohorts, indicating a potential therapeutic target. Our study showed that PDIA3 was associated with tumor malignant characteristics and could mediate the migration of M2 macrophages in various tumor types. PDIA3 could be a promising target to achieve tumor control and improve the immune response on a pan-cancer scale.

Gynecologic Cancer InterGroup CA125 response has a high negative predictive value for CHK1 inhibitor RECIST response in recurrent ovarian cancer

We investigated the association of CA125 response with prognosis and RECIST response/progressive disease (PD) criteria in recurrent high grade serous ovarian cancer (HGSOC) patients treated with a cell cycle checkpoint kinase 1 inhibitor (CHK1i), prexasertib. 81 patients had measurable disease per RECISTv1.1, of which 72 and 70 were measurable by Gynecologic Cancer InterGroup (GCIG) CA125 response and PD criteria, respectively. Univariate and multivariate analyses showed that GCIG CA125 response (n = 32) is associated with improved progression-free survival (PFS) and overall survival (OS) compared to no GCIG CA125 response (n = 40) (median PFS 8.0 vs. 3.5 months [HR: 0.30, 95% CI: 0.18–0.51, p < 0.0001]; median OS 19.8 vs. 10.0 months [HR: 0.38, 95% CI: 0.23–0.64, p < 0.001]) independent of BRCA mutation status, platinum-sensitivity, previous PARP inhibitor therapy, ECOG performance status, and FIGO stage. Notably, GCIG CA125 response had a high negative predictive value (NPV: 93%, 95% CI: 80–98), but poor positive predictive value (PPV: 53%, 95% CI: 35–71) in predicting RECIST response. CA125 PD criteria also showed poor concordance with RECIST PD (PPV 56%, 95% CI: 40–71; NPV 33%, 95% CI: 17–54). Therefore, serum CA125 may be useful as a highly accessible prognostic and predictive biomarker to CHK1i therapy in recurrent HGSOC.