bluuebunny/crossref_metadata_2025_split huggingface dataset:
B-341 Analytical Performances of Homogeneous Mobility Shift Assay for Infliximab and Biosimilars and Resulting Exposure Assessments in Large Cohort of Patients With Inflammatory Bowel Diseases
Authors: McFarland J , Tsang J , Ho J , McLachlan O , Gowhari M , Hughes P , Dervieux T 
Published: September 2023

Abstract

Background
Biosimilar for infliximab (IFX) are currently available for the treatment of various immune mediated inflammatory diseases including inflammatory bowel disease (IBD). We have validated the homogenous mobility shift assay (HMSA) for IFX biosimilars and describe exposure from a large population of patients with IBD treated with IFX and biosimilars.

Methods
Validation of the biosimilars, infliximab-dyyb (Inflectra®) and infliximab-abda (Renflexis®), was conducted in a reference clinical laboratory (Prometheus Laboratories, Inc.) for performance equivalence to the 1st international World Health Organization (WHO) IFX standard (16/170) by HMSA. The evaluated performance characteristics consisted of accuracy, precision, sensitivity, specificity, range, and linearity using spiked human serum. Following validation and implementation in the clinical laboratory, the drug median with interquartile range (IQR) and antibody to drug (ATI) prevalence and percentage relative to low-titer antibody cut-point of 10 U/mL (Am J Gastroenterol 2021;00:1-12), using de-identified patients, was evaluated by comparing treatment with IFX or the two validated biosimilars.

Results
The reportable range for the biosimilars was 0.98 μg/mL (precision: 5.5% CV; accuracy: 110.7% recovery) to 34 µg/mL (precision: 6.3% CV; accuracy: 105.4% recovery). Biosimilar intra-day, inter-day precision (CV) and accuracy (% recovery) across the reportable range were 3.8%, 3.6% and 105.1%, respectively. Furthermore, HMSA calibrated with IFX originator or biosimilar showed congruent results when compared to calibration with the WHO standard for the determination of drug concentrations using 20 clinical samples spanning the reportable range (Fig. 1). Median drug concentrations with IQR were 10.9 µg/mL (4.8–19.7 µg/mL) for infliximab originator, 9.8 µg/mL (3.9–18.1) for infliximab-dyyb, and 9.5 µg/mL (3.6–18.3) for infliximab-abda over a three-year period of testing, which also demonstrated similar ATI positivity rates.

Conclusion
HMSA is validated to be used as a tool for therapeutic drug monitoring (TDM) of patients treated with IFX originator and biosimilars.
B-364 Inhibition of Hypoxia-Inducible Factor-1a (HIF-1 a) Provides a Therapeutic Approach for Hepatocellular Carcinoma (HCC)
Authors: Alghamdi U M 
Published: September 2023

Abstract

Background
The most frequent type of primary liver cancer in adults is hepatocellular carcinoma (HCC) which is the third-highest cause of cancer-related death worldwide. Globally, people die from liver cancer each year, with HCC accounting for around 90% of those deaths, making it a serious public health concern. Cirrhosis, hepatitis B, hepatitis C, and non-alcoholic fatty liver disease are all high-risk factors for HCC development. In addition, HCC is one of the most frequent solid tumors found in humans. Due to insufficient blood supply, these solid tumors usually are devoid of oxygen and nutrients. A reduction in oxygen concentration results in the formation of a hypoxic environment that downregulates the metabolic process and is fatal to cancer cells. To circumvent this barrier to growth, cancer cells produce hypoxia-inducible factor-1 (HIF-1), which alters their metabolic pathways and allows them to survive. HIF-1alpha (HIF-1α), a cytoplasmic subunit of HIF-1 can be overexpressed in hypoxic conditions. HCC cells cannot proliferate under hypoxia without a high level of HIF-1α expression, making it as a potential cancer treatment target. Using the LOPAC (Library of Pharmacologically Active Compounds) drug library, we have identified multiple drug molecules that inhibit the expression of HIF-1α.

Methods
We constructed specific SK-HEP-1 cells, a human liver cancer cell line, expressing the luciferase reporter gene under the promoter of HIF-1α. By using the cells, we screened the (LOPAC) library. Other bioanalytical methods were used to confirm and analyze identified candidates.

Results
We successfully identified several compounds that are able to inhibit HIF-1α expression by using luciferase activity assays and Western blot analysis (WB). Further investigation was conducted to determine the molecular mechanism and function for one of the drug candidates, termed as UZ-1, in inhibiting HIF-1α in HCC by using the MTT assay and WB. UZ-1, an antirheumatic agent, showed a strong inhibitory effect on the expression of HIF-1α in SK-HEP-1 cells. In addition, it suppressed the signaling pathways associated with HIF-1α, leading to the apoptosis of HCC cells.

Conclusion
The UZ-1 molecule inhibits HIF-1α expression, as a result, and displays anticancer function in HCC cells through inducing apoptosis. Our result suggests that UZ-1 may be a potential drug candidate for the treatment of HCC.
B-365 Serum MAGE-A3 and MAGE-A4 Protein Levels as Potential Prognostic Biomarkers for Lung Cancer
Authors: Kong D , Gonzalez R , Yom J , Guo Z , Qu T , Hu X , Ren Q , Wu Z , Zewdu E , Guo H , Gilmore B , Zhao Z , Liu X , Fu W 
Published: September 2023

Abstract

Background
Melanoma-associated antigen 3 (MAGE-A3) and MAGE-A4 are members of Melanoma Antigen Gene (MAGE) family, which have restricted expression to the testis and are abnormally expressed in cancer cells. MAGE-A3 and MAGE-A4 are overexpressed in lung cancer and have been shown to be associated with cancer progression and poor prognosis. Elevated MAGE-A4 protein level in lung cancer serum samples has been reported in the literature, however, it is unclear whether MAGE-A3 protein can be detected in serum samples of lung cancer patients.

Methods
We developed human MAGE-A3 and MAGE-A4 sandwich ELISA kits and used them to measure serum MAGE-A3 and MAGE-A4 protein levels in 21 lung cancer patients and 30 non-cancer controls.

Results
Serum MAGE-A3 protein was detected in all 21 lung cancer patients (range: 34 to 78871 pg/mL, mean: 5600 pg/mL) and was significantly elevated compared to non-cancer controls (range: 23–308 pg/mL, mean: 140 pg/mL) (P &lt; 0.05). Serum MAGE-A4 protein was detected in 5 of 21 (24%) lung cancer patients (range: 280 to 35096 pg/mL, mean: 1819 pg/mL), and the samples with high serum MAGE-A4 concentration matched those with high serum MAGE-A3 concentration. Serum MAGE-A4 protein was not detectable in non-cancer controls.

Conclusion
Our findings suggest that serum MAGE-A3 and MAGE-A4 may serve as potential prognostic biomarkers for lung cancer. The detection of elevated serum MAGE-A3 and MAGE-A4 in lung cancer patients indicates their specificity for the disease. Larger studies with more samples, different cancer stages, and longer follow-up are needed to validate these results and establish the clinical utility of serum MAGE-A3 and MAGE-A4 levels as prognostic markers for lung cancer. If further validated, these biomarkers could aid in early diagnosis and better management of lung cancer.
B-367 Analytical Validation of New CLIA Based TPS Assay as a Biomarker in Cancer Management
Authors: Jagarlamudi K , Damico Y , Pellegrini P , Torstensson M , Xia Z , Xue L 
Published: September 2023

Abstract

Background
Tissue polypeptide-specific antigen (TPS) has been described as a potentially useful serum marker of tumor activity in adult epithelial tumors such as breast, ovarian, prostate, and other malignancies. Here we developed and analytically validated Chemiluminescence immunoassay (CLIA) for TPS on the CIA series analyzer and FOSUN series analyzer in collaboration with Jiangsu ZECEN Biotech Co., Ltd (Jiangsu and Beijing, China).

Methods
The TPS-CLIA relies on two monoclonal antibodies generated against peptides that bind to cytokeratin 18 (CK18). The TPS-CLIA assay has been analytically validated and a reference range was established by using sera from blood donors (n = 101), and potential applicability was demonstrated in sera from patients with different malignant diseases (n = 54). The same serum samples were also analyzed with TPS-ELISA for comparison.

Results
The TPS-CLIA had a limit of the blank of 6 U/L with a limit of detection of 10 U/L and a dynamic range of 10–1200 U/L. The total assay precision was below 20% and no hook effect was observed up to 3265 U/L. Linear dilution of high endogenous TPS sera at 1:4 to 1:256 had shown a recovery in the range of 85%–115%. No significant interference was observed with bilirubin, hemoglobin, and triglycerides (&lt;10%, Table 1). The assay binds to CK18 and no cross-reactivity was observed with CK8 or CK19. The cut-off value (95% CI) based on the blood donor sera was 80 U/L (range = 10–116). There was a significant correlation between TPS-CLIA and TPS-ELISA assay (r = 0.93; P &lt; 0.0001) in different malignancies. More analytical parameters of TPS-CLIA are summarized as shown in Table 1.

Conclusion
The new TPS-CLIA provides a unique, robust, and convenient method for measuring cytokeratin 18 levels in serum. This can improve the clinical applications of TPS as a biomarker in cancer management.
B-382 Accurate and Early Detection of Colorectal Cancer Using a Multilocus DNA Methylation Markers-based Testing in Peripheral Blood Mononuclear Cells
Authors: Wang C , Li P , Xie Y 
Published: September 2023

Abstract

Background
An effective blood-based method for the diagnosis of colorectal cancer (CRC) has not yet been developed. Molecular alterations of immune cells occur early in tumorigenesis, providing the theoretical underpinning for early cancer diagnosis. Therefore, we aimed to develop an effective multi-molecular simultaneous detection method based on peripheral blood mononuclear cells (PBMCs) to improve the diagnosis of early-stage CRC.

Methods
Candidate DNA methylation markers were first identified from PBMCs using the Infinium MethylationEPIC array in the discovery phase (Shandong cohort I, n = 100) and further validated via pyrosequencing and targeted bisulfite sequencing in validation phase (Shandong cohort II, n = 202). Then, a single-tube multiplex methylation-specific quantitative PCR assay (multi-msqPCR) for simultaneous detection of five markers was established in a pilot study. After that, a CRC prediction model (CPM) based on DNA methylation and multi-msqPCR method was construct and its diagnostic performance were evaluated using the area under the receiver operating characteristic curve (AUROC) in our multicenter cohort (n = 595).

Results
Five discriminative DNA methylation markers identified by Illumina 850K microarray were successfully validated to diagnose early-stage CRC. Multi-msqPCR showed a better discriminative performance and 10-time lower detection limit than single-molecule detection in early-stage CRC. The cross-validated AUROC for CPM for early-stage CRC was 0.91 (sensitivity = 81.18%; specificity = 89.39%), significantly higher than CEA (AUROC = 0.62). CPM assay also yielded a high degree of discrimination for advanced adenoma (AA) cases (AUROC = 0.85; sensitivity = 63.04%; specificity = 89.39%). Besides, detecting CPM in multiple cancer types implied a CRC-specific diagnostic value. Our follow-up data also demonstrated that CPM could detect early-stage CRC up to 2 years before current traditional diagnostic methods.

Conclusions
CPM, in combination with epigenetic biomarkers and the multi-msqPCR method, was promising, cost-effective, and easily implementable for routine clinical diagnosis of early-stage CRC.
B-383 Exosomal PRPSAP1 in Plasma Predicts Microvascular Invasion in Hepatocellular Carcinoma
Authors: Xin Z , Zhou J , Chen H , Song M , Jiao L , Ying B 
Published: September 2023

Abstract

Background
Microvascular invasion (MVI), a critical predictor of postoperative tumor recurrence in hepatocellular carcinoma (HCC), is only detectable by histopathological examination of the surgical specimen. Prediction of MVI before surgery is of great significance to prognosis, especially by non-invasive means. Here, we report that exosome-derived mRNA in plasma can be promising biomarkers for MVI preoperatively.

Methods
Patients with initially suspected HCC who were undergoing hepatectomy were prospectively recruited with preoperative peripheral blood collection and followed up. Exosomal mRNA profiling was performed using RNA sequencing in the discovery cohort, and the edgeR package in R software was used to screen out significantly differential expression exosomal mRNAs between MVI and non-MVI groups. Multiplex droplet digital PCR (ddPCR) technology was utilized to verify filtered exosomal mRNAs in the validation cohort.

Results
A total of 131 HCC patients were enrolled with 37 in the discovery cohort and 94 in the validation cohort. RNA-sequencing data identified six candidate exosomal mRNAs (ZC3H3, RSAD2, PRPSAP1, HOXA2, CHPM4A and KCTD10) as potential predictors for MVI. In the validation cohort, expression levels of PRPSAP1 and HOXA2 were slightly higher and the expression level of CHMP4A was slightly lower in the MVI group than the non-MVI one, which were consistent with the discovery cohort though without statistically significant difference (P &gt; 0.05). Further analysis between MVI number&gt;5 and non-MVI patients validated that the expression level of exosomal PRPSAP1 was significantly higher in MVI number&gt;5 patients (0.147 vs 0.070, P = 0.035). Altogether, exosomal PRPSAP1 in plasma was a promising biomarker predicting MVI for HCC patients.

Conclusion
We validated for the first time that high level expression of exosome-derived PRPSAP1 can preoperatively predict MVI, especially with the number &gt;5, to improve prognosis.
B-384 Genetic Variations Predict Severe Immunotherapy-related Adverse Events for PD-1/PD-L1 Inhibitors
Authors: Xin Z , You L , Na F , Li J , Chen M , Song J , Bai L , Chen J , Zhou J , Ying B 
Published: September 2023

Abstract

Background
PD-1/PD-L1 inhibitors have brought remarkable benefits but can cause profound immune-related adverse events (irAEs), especially life-threatening toxicities. The host immunogenetic background is likely to play a role in irAE susceptibility. Here, we identified the variants that could predict severe irAEs in patients with cancer.

Methods
Patients with solid tumors receiving PD-1/PD-L1 blockade were recruited and followed up. Genes considered pivotal contributors to tumor-immunity and autoimmune diseases were screened out via Protein-Protein Interaction network and Cytoscape. Consequently, thirty-nine variants in eighteen genes were genotyped using the multiplex genotyping assay. Association analysis between those variants and severe irAEs (G3-G5 grades) as well as irAEs-free survival was performed.

Results
Two immunogenetic variants as predictors of severe irAEs were identified. The A allele of ADAD1 rs17388568 (OR = 2.599, 95% CI = 1.355–4.983, P = 0.003) increased the risk of severe irAEs, while the G allele of IL6 rs1800796 (OR = 0.425, 95% CI = 0.205–0.881, P = 0.018) protected patients from severe irAEs. In multivariate Cox regression analysis, ADAD1 rs17388568 (AA vs AG or GG: HR = 0.11, 95% CI = 0.025–0.49, P = 0.004) and IL6 rs1800796 (GG or GC vs CC: HR = 3.10, 95% CI = 1.315–7.29, P = 0.01) were also independent variables for severe irAEs-free survival.

Conclusion
We identified two immunogenetic polymorphisms associated with severe irAEs in PD-1/PD-L1 blockade-treated tumor patients at the first time, and they may serve as promising predictive biomarkers.
B-388 Clinical Performance of Xpert BCR-ABL Ultra Assay for Isoform p210 Quantitation
Authors: Marques F K , Mendonça C P , Zauli D A 
Published: September 2023

Abstract

Background
Chronic myelogenous leukemia (CML) is one of the most common hematologic neoplasms. More than 95% of patients with CML have the distinctive Philadelphia chromosome (Ph1) that results from a translocation between the chromosomes 9 and 22, and consequently in the BCR::ABL1 fusion gene. This fusion gene produces a tyrosine kinase with deregulated activity that plays a key role in the development of CML. Monitoring BCR::ABL transcript levels in patients on tyrosine kinase inhibitor (TKI) therapy using real-time quantitative PCR is standard of care in the management of CML patients. The test utilizes a quantitative, real-time reverse transcription polymerase chain reaction (RT-qPCR) to measure BCR::ABL1 to ABL1 percent ratios on the International Scale (%IS), in t(9;22) positive CML patients during monitoring of treatment with TKIs. In this context, this study evaluated clinical performance of the Xpert® BCR-ABL Ultra assay for quantitation of BCR::ABL1 p210 transcripts.

Methods
The clinical performance of assay was evaluated by comparison to an RT-qPCR assay routinely used in our institution, which also detects and quantifies the mRNA transcripts for the p210 translocation types and uses the ABL gene as an endogenous control. In total, 30 fresh peripheral blood samples of CML patients with the level of BCR::ABL1 transcripts (international scale, IS) between &gt;50% and undetectable were enrolled in this study. All steps of protocols were performed according to manufacturer ́s instructions.

Results
The comparison of two assay revealed consistente molecular response (MR) level. Linear regression analysis showed high correlation between the assays (R2 = 0.974, P &lt; 0.0001) The slope of regression curve were not significantly different from the value of 1 (1.003; 95% CI, range 0.943–1.069). The evaluation of MR level was identical in 21/28 (75%) samples. Two samples were excluded from the study due to failure to control ABL1 (Ct &gt; 18). The median of ABL1 copies per sample was 66 011 copies (range 20 010–236 171) for conventional RT-qPCR assay. Xpert BCR-ABL Ultra reports %IS (MR), but this test does not report ABL1 copy numbers. If the Xpert BCR-ABL Ultra test reports a positive or negative result and the ABL1 Ct value is below 18, a minimum of 32 000 ABL1 copy numbers is guaranteed in the reaction. The BCR::ABL1 negativity was concordant in 2/8 samples.

Conclusion
We showed that the results Xpert® BCR-ABL Ultra assay (MR) are in good correlation with the results of RT-qPCR conventional method.The Xpert® BCR-ABL Ultra assay simplifies the generation of results by integrating nucleic acid extraction, amplification, and quantification of the BCR::ABL1 p210 transcripts in peripheral blood specimens. The assay turn-around-time is approximately 3 h. This does not differentiate between b2a2 or b3a2 fusion transcripts.This assay is unable to detect BCR::ABL1 p190 or other rarer translocations.
Uniformizations of Compact Sasakian Manifolds
Authors: Kasuya Hisashi , Miyatake Natsuo 
Published: September 2023

Abstract
We give a criterion for compact Sasakian manifolds to be deformed to Sasakian manifolds, which are locally isomorphic to circle bundles of anti-canonical bundles over Hermitian symmetric spaces as a Sasakian analogue of Simpson’s uniformization results related to variations of Hodge structure and Higgs bundles.
Reexamining the Minimum Sweat Rate Requirement for Sweat Chloride Testing
Authors: Omosule Catherine L , Dietzen Dennis J , Roper Stephen M 
Published: September 2023

Abstract

Background
Guidelines for sweat chloride testing endorse a minimum sweat rate for reporting results. Bilateral sweat collection is recommended, but if both sites fail to meet the minimum rate (quantity not sufficient, QNS), the test should be repeated. In this study, we examine the correlation between sweat rate and sweat chloride concentration ([Cl−]), assess the accuracy of specimens collected at suboptimal rates, and investigate the use of pooled bilateral specimens for chloride measurement.

Methods
Pearson correlation was employed to analyze the relationship between sweat rate and chloride concentration, [Cl−], in 674 macroduct collections. Weighted kappa was evaluated to determine cystic fibrosis (CF) diagnostic classification concordance for 18 tests with paired arms above vs below the minimum sweat rate. Deming regression was applied to compare [Cl−] from pooled bilateral specimens vs neat specimens in 27 collections with residual volume available after clinical testing.

Results
Pearson correlation of sweat rate vs [Cl−] was minimal (r = −0.0735) across specimens with varying rates and [Cl−]. There was substantial agreement in CF diagnostic classification between arms for bilateral collections with discordant sweat rates. Regression analysis of [Cl−] in pooled vs nonpooled specimens revealed a slope of 0.984 and an intercept of 0.796.

Conclusions
Negligible correlation of sweat rate and [Cl−] suggests the minimum sweat rate for macroduct collectors may be overly stringent. Reporting of [Cl−] in specimens with ≥10 µL (rate ≥0.3 µL/min) may reduce QNS rates without compromising diagnostic accuracy. Preliminary data suggests pooling of bilateral collections may be a feasible option to achieve the required volume for testing.
Orienting attention across binocular disparity
Authors: Caziot Baptiste , Rolfs Martin , Backus Benjamin T 
Published: September 2023

AbstractThe spatial distribution of covert visual attention following an exogenous cue is often described as a spotlight, which disregards depth. Here, we study the orienting of attention across binocular disparity, a key depth cue in primates. A small Gabor patch target was displayed at ±12-arcmin horizontal offset in each eye independently, resulting in four possible 3D locations. With some latency relative to target onset (0–300 ms), an attentional cue was displayed at one of five binocular locations, resulting in various combinations of relative azimuth (horizontal position) and disparity (depth). Observers’ task was to discriminate the orientation of the target. Observers’ performance decreased as the relative azimuth between the cue and the target increased. Performance also decreased with the difference in disparity, even when the azimuth remained constant. Performance varied with the delay between the cue and the target and was maximal between 100 and 150 ms. The orienting of attention in azimuth and depth followed the same time course. We mapped the 3D shape of attentional focus over time and found that the spatial envelope was approximately a Gaussian modulated in time. These results could not be explained by monocular confounds nor by eye movements. We conclude that exogenous cues direct attention not only to their visual direction but also to their depth and that binocular disparity is sufficient to define that depth. The identical time course and interaction between azimuth and depth suggest a shared mechanism, and therefore that visual attention to spatial location is an intrinsically 3D process.