Case Report: Favorable Response and Manageable Toxicity to the Combination of Camrelizumab, Oxaliplatin, and Oral S-1 in a Patient With Advanced Epstein–Barr Virus-Associated Gastric Cancer

Some pertinent studies have demonstrated that Epstein–Barr virus-associated gastric cancer (EBVaGC) patients showed a favorable clinical outcome to immunotherapy and Epstein–Barr virus (EBV)-positive status might be a potential biomarker for immunotherapy in gastric cancer (GC). However, knowledge of given exposure to EBVaGC to the first-line immunotherapy is largely inadequate. Moreover, whether camrelizumab can be as effective as other PD-1 inhibitors in the treatment of advanced EBVaGC has not been reported. We report a case of advanced EBVaGC patient with a positive expression of PD-L1, enriched PD-L1+CD68+macrophages, and high TMB who had a long-term partial response and manageable toxicity to the combined approach of camrelizumab (a novel PD-1 inhibitor) and oxaliplatin plus oral S-1 (SOX). As the first-line treatment of advanced EBVaGC patients, camrelizumab combined with SOX regimen may provide a novel combined approach with favorable response and manageable safety. Combination of multiple biomarkers could have a higher effective predictive capacity to immunotherapy. Integrated treatment (chemo-immunotherapy and radiotherapy) might be the optimal strategy for patients with oligometastasis. It deserves prospective research to further validate the efficacy.

LCK and CD3E Orchestrate the Tumor Microenvironment and Promote Immunotherapy Response and Survival of Muscle-Invasive Bladder Cancer Patients

Background: Studies have demonstrated the significance of multiple biomarkers for bladder cancer. Here, we attempt to present biomarkers potentially predictive of the prognosis and immunotherapy response of muscle-invasive bladder cancer (MIBC).Method: Immune and stromal scores were calculated for MIBC patients from The Cancer Genome Atlas (TCGA). Core differential expression genes (DEGs) with prognostic value were identified and validated using an independent dataset GSE31684. The clinical implications of prognostic genes and the inter-gene correlation were presented. The distribution of tumor-infiltrating immune cells (TICs), the correlation with tumor mutation burden (TMB), and the expression of eight immune checkpoint–relevant genes and CD39 were accordingly compared. Two bladder cancer cohorts (GSE176307 and IMvigor210) receiving immunotherapy were recruited to validate the prognostic value of LCK and CD3E for immunotherapy.Results: 361 MIBC samples from TCGA revealed a worse overall survival for higher stromal infiltration (p = 0.009) but a better overall survival for higher immune infiltration (p = 0.042). CD3E and LCK were independently validated by TCGA and GSE31684 to be prognostic for MIBC. CD3E was the most correlative gene of LCK, with a coefficient of r = 0.86 (p < 0.001). CD8+ T cells and macrophage M1 are more abundant in favor of a higher expression of CD3E and LCK in MIBC and across pan-cancers. Immune checkpoints like CTLA4, CD274 (PD-1), and PDCD1 (PD-L1) were highly expressed in high-CD3E and high-LCK groups for MIBC and also for pan-cancers, except for thymoma. LCK and CD3E had a moderate positive correlation with CD39 expression. Importantly, high-LCK and high-CD3E groups had a higher percentage of responders than the low-expression groups both in GSE176307 (LCK: 22.73vs. 13.64%, CD3E: 22.00 vs. 13.16%) and IMvigor210 cohorts (LCK: 28.19 vs. 17.45%, CD3E: 25.50 vs. 20.13%).Conclusion: CD3E and LCK were potential biomarkers of MIBC. CD3E and LCK were positively correlated with several regular immunotherapy biomarkers, which is supported by real-world outcomes from two immunotherapy cohorts.

Multiple Biomarker Responses in Female Catfish (Clarias Gariepinus) Exposed to Acetaminophen

Acetaminophen is one of the most commonly detected Analgesics and pain killer drug in freshwater environments. This study evaluated the possible multi-toxic effects of environmentally relevant concentrations (15.5, 25.5, 35.5 and 45.5µg/L) of acetaminophen in Clarias gariepinus fish exposed for 28 days using multiple biomarkers. Hepatosomatic index (HIS) and condition factor (K) of acetaminophen–exposed group were not different from the control. The superoxide dismutase (SOD) activity increased significantly at 15.5 and 35.5µg/L and Catalase (CAT) activity in all acetaminophen-exposed groups barely showed an upward trend. The concentration of glutathione S-transferase (GST) activities was not different from the control. Glutathione peroxidase (GPx) activities increased at all concentrations when compared to the control group. There were general inhibitions of Acetylcholinesterase (AChE) activities in all exposed groups including the control. Total antioxidant capacity (TAC) increased significantly at 25.5 and 45.5µg/L and Interluekin-6 (IL-6) showed non-significant increases in all exposed concentrations. Acetaminophen exposure caused non-significant increases in the activities of C reactive protein (CRP). White blood cells (WBC) and lymphocytes (LYM counts) were significant reduced. Acetaminophen induced significant changes in hormones of the hypothalamic-pituitary-gonad (HPG) axis (17β-Estradiol and Testosterone) and vitellogenin (Vtg) synthesis at 45.5µg/L. Histopathological alterations in the liver was evident of apoptotic hyperplasia, sinusoidal congestion and necrosis of the hepatocytes and was concentration dependent. Acetaminophen exposure to the fish gills enhanced the fusion and shortening of some filaments, hyperplasia of the epithelia gills cells, aneurism, congestion and epithelia rupture of the gills. Gonad examination showed acetaminophen exposure triggered the occurrence of intersex in 25.5, 35.5 and 45.5µg/L. The collaborative biomarkers used in this study showed the multiple impacts of acetaminophen on the physiology of C. gariepinus. Multivariate statistical analysis indicated that fish in the control groups exhibited a distinctly response from the acetaminophen-exposed fish and that over 95% of the biomarkers significantly contribute to discriminate between the acetaminophen-exposed fish and the control group. Our research provides evidence supporting the use of multiple-biomarker approach to evaluate the health status of C. gariepinus in future studies.

Environmental health methods

Both host and environmental factors are involved in the development of human diseases. Environmental causes of disease include physical, chemical, biological, behavioural, and social factors. Consistent findings in both observational and interventional studies at aggregate and individual levels provide strong evidence of causation between human diseases and environmental agents. They are illustrated by the elucidation of the pleiotropic health effects of arsenic in drinking water and the multifactorial aetiology of hepatocellular carcinoma caused by viral hepatitis. Molecular and genomic biomarkers are used to explore the time-dependent host–environment interaction in the natural history of human diseases. They include dosimetry of exposure to environmental agents; the health outcomes at molecular, cellular, and histological levels; and the genetic and acquired susceptibility. Risk calculators combining multiple biomarkers are developed for the prediction of long-term disease risk. Global partnerships need to be strengthened to achieve interrelated goals of human health, environmental sustainability, and socioeconomic development.

Cerebrospinal fluid and blood biomarkers in the diagnostic assays of Alzheimer’s disease

The anti-amyloid-[Formula: see text] (anti-A[Formula: see text]) fibrils and soluble oligomers antibody aducanumab were approved to effectively slow down the progression of Alzheimer’s disease (AD) at higher doses in 2019, reaffirming the therapeutic effects of targeting the core pathology of AD. A timely and accurate diagnosis in the prodromal or pre-dementia stage of AD is essential for patient recruitment, stratification, and monitoring of treatment effects. AD core biomarkers amyloid-[Formula: see text] (A[Formula: see text]), total tau (t-tau), and phosphorylated tau (p-tau) have been clinically validated to reflect AD-type pathological changes through cerebrospinal fluid (CSF) measurement or positron-emission tomography (PET) and found to have high diagnostic performance for AD identification in the stage of mild cognitive impairment. The development of ultrasensitive immunoassay technology enables AD pathological proteins such as tau and neurofilament light (NFL) to be measured in blood samples. However, combined biomarker detection or targeting multiple biomarkers in immunoassays will increase detection sensitivity and specificity and improve diagnostic accuracy. This review summarizes and analyzes the performance of current detection methods for early diagnosis of AD, and provides a concept of detection method based on multiple biomarkers instead of a single target, which may become a potential tool for early diagnosis of AD in the future.

Wave-shaped microfluidic chip assisted point-of-care testing for accurate and rapid diagnosis of infections

Background: Simultaneous and timely detection of C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6) provides effective information for the accurate diagnosis of infections. Early diagnosis and classification of infections increase the cure rate while decreasing complications, which is significant for severe infections, especially for war surgery. However, traditional methods rely on laborious operations and bulky devices. On the other hand, point-of-care (POC) methods suffer from limited robustness and accuracy. Therefore, it is of urgent demand to develop POC devices for rapid and accurate diagnosis of infections to fulfill on-site militarized requirements.Methods: We developed a wave-shaped microfluidic chip (WMC) assisted multiplexed detection platform (WMC-MDP). WMC-MDP reduces detection time and improves repeatability through premixing of the samples and reaction of the reagents. We further combined the detection platform with the streptavidin-biotin (SA-B) amplified system to enhance the sensitivity while using chemiluminescence (CL) intensity as signal readout. We realized simultaneous detection of CRP, PCT, and IL-6 on the detection platform and evaluated the sensitivity, linear range, selectivity, and repeatability. Finally, we finished detecting 15 samples from volunteers and compared the results with commercial ELISA kits.Results: Detection of CRP, PCT, and IL-6 exhibited good linear relationships between CL intensities and concentrations in the range of 1.25-40 μg/mL, 0.4-12.8 ng/mL, and 50-1600 pg/mL. The limit of detection (LOD) of CRP, PCT, and IL-6 were 0.54 μg/mL, 0.11 ng/mL, and 16.25 pg/mL, respectively. WMC-MDP is capable of good adequate selectivity and repeatability. The whole detection procedure takes only 22 minutes that meets the requirements of a POC device. Results of 15 samples from volunteers were consistent with the results detected by commercial ELISA kits.Conclusion: WMC-MDP allows simultaneous, rapid, and sensitive detection of CRP, PCT, and IL-6 with satisfactory selectivity and repeatability, requiring minimal manipulation. However, WMC-MDP takes advantage of being a microfluidic device showing the coefficients of variation less than 10% enabling WMC-MDP to be a type of POCT. Therefore, WMC-MDP provides a promising alternative to point-of-care testing (POCT) of multiple biomarkers. We believe the practical application of WMC-MDP in militarized fields will revolutionize infection diagnosis for soldiers.