Paclitaxel-induced Immune Dysfunction and Activation of Transcription Factor AP-1 Facilitate Hepatitis B Virus Replication.

Background and Aims: Hepatitis B virus (HBV) reactivation is commonly observed in individuals with chronic HBV infection undergoing antineoplastic drug therapy. Paclitaxel (PTX) treatment has been identified as a potential trigger for HBV reactivation. This study aimed to uncover the mechanisms of PTX-induced HBV reactivation in vitro and in vivo, which may inform new strategies for HBV antiviral treatment. Methods: The impact of PTX on HBV replication was assessed through various methods including enzyme-linked immunosorbent assay, dual-luciferase reporter assay, quantitative real-time PCR, chromatin immunoprecipitation, and immunohistochemical staining. Transcriptome sequencing and 16S rRNA sequencing were employed to assess alterations in the transcriptome and microbial diversity in PTX-treated HBV transgenic mice. Results: PTX enhanced the levels of HBV 3.5-kb mRNA, HBV DNA, HBeAg, and HBsAg both in vitro and in vivo. PTX also promoted the activity of the HBV core promoter and transcription factor AP-1. Inhibition of AP-1 gene expression markedly suppressed PTX-induced HBV reactivation. Transcriptome sequencing revealed that PTX activated the immune-related signaling networks such as IL-17, NF-κB, and MAPK signaling pathways, with the pivotal common key molecule being AP-1. The 16S rRNA sequencing revealed that PTX induced dysbiosis of gut microbiota. Conclusions: PTX-induced HBV reactivation was likely a synergistic outcome of immune suppression and direct stimulation of HBV replication through the enhancement of HBV core promoter activity mediated by the transcription factor AP-1. These findings propose a novel molecular mechanism, underscoring the critical role of AP-1 in PTX-induced HBV reactivation.

Long noncoding RNA MyD88 functions as a promising diagnostic biomarker in hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the most frequent malignancies. Alpha-fetoprotein (AFP) has some limitations in diagnosing early HCC. Recently, long noncoding RNAs (lncRNAs) showed great potential as tumor diagnostic biomarkers, and lnc-MyD88 was previously identified as a carcinogen in HCC. Here, we explored its diagnostic value as a plasma biomarker. Materials and methods: Quantitative real-time PCR was adopted to detect lnc-MyD88 expression in plasma samples of 98 HCC patients, 52 liver cirrhosis (LC) patients, and 105 healthy people. The correlation between lnc-MyD88 and clinicopathological factors was analyzed through chi-square test. The receiver operating characteristic (ROC) curve was used to analyze the sensitivity, specificity, Youden index, and area under the curve (AUC) of lnc-MyD88 and AFP alone and in combination for the diagnosis of HCC. The relationship between MyD88 and immune infiltration was analyzed by single sample gene set enrichment analysis (ssGSEA) algorithm. Results: Lnc-MyD88 was highly expressed in plasma samples of HCC and hepatitis B virus (HBV)-associated HCC patients. Lnc-MyD88 had better diagnostic value than AFP in HCC patients using healthy people or LC patients as control (healthy people, AUC: 0.776 vs. 0.725; LC patients, AUC: 0.753 vs. 0.727). The multivariate analysis showed that lnc-MyD88 had great diagnostic value for distinguishing HCC from LC and healthy people. Lnc-MyD88 had no correlation with AFP. Lnc-MyD88 and AFP were independent diagnostic factors for HBV-associated HCC. The AUC, sensitivity, and Youden index of the combined diagnosis of lnc-MyD88 and AFP combined were higher than those of lnc-MyD88 and AFP alone. The ROC curve of lnc-MyD88 for the diagnosis of AFP-negative HCC was plotted with a sensitivity of 80.95%, a specificity of 79.59%, and an AUC value of 0.812 using healthy people as control. The ROC curve also presented its great diagnostic value using LC patients as control (sensitivity: 76.19%, specificity: 69.05%, AUC value: 0.769). Lnc-MyD88 expression was correlated with microvascular invasion in HBV-associated HCC patients. MyD88 was positively correlated with infiltrating immune cells and immune-related genes. Conclusion: The high expression of plasma lnc-MyD88 in HCC is distinct and could be utilized as a promising diagnostic biomarker. Lnc-MyD88 had great diagnostic value for HBV-associated HCC and AFP-negative HCC, and it had higher efficacy in combination with AFP.

Study of the synergistic influence of zwitterionic interactions and graphene oxide on water diffusion mechanism and mechanical properties in hybrid hydrogel network.

Hybrid hydrogels based on n-isopropylacrylamide, zwitterionic comonomer, and graphene oxide were synthesized to study their physical and mechanical properties. The compositional variation largely influenced the swelling characteristics of the hybrid hydrogels compared to mechanical properties, i.e., elongation and compression. Additionally, Rheometric swelling measurements on the swollen hydrogels were performed until they reached equilibrium showed a very low phase angle δ indicating strong covalent network, which intrun increases with increasing content of zwitterions and GO. Swelling kinetics were studied and found to follow Fickian dynamics, albeit zwitterion-containing gels showed a peculiar 2-step swelling pattern. Interestingly, differences in the swelling mechanism are also clear for the hydrogels with 2D GO (Graphene oxide) nano-fillers from its 1D nano-filler CNTs (Carbon nanotubes). In elongation, the samples break in a brittle fashion at Hencky strains εmax around 0.4-0.65 with the maximum stress being observed for samples with high Zw-content and 0.2% GO, which can be explained by the stress-rising properties of sharp edges of GO. In contrast, the data in compression profits from higher GO-contents as crack growth is less important in this deformation mode. This work will contribute to future composite gel applications.

Pancreatic Tuberculosis mimicking as a Pancreatic Mass Lesion.

Tuberculosis is a global health problem and commonly affects the respiratory system. The involvement of the pancreas in this disease is a rare event. We hereby report a case of a young male who presented with right hypochondrial pain along with significant weight loss. Further workup revealed a raised erythrocyte sedimentation rate along with a pancreatic mass lesion on the CT scan. Endoscopic ultrasound-guided biopsy of the pancreatic lesion revealed evidence of caseation necrosis along with epithelioid granuloma, findings suggestive of tuberculosis. He was started on anti-tuberculous therapy for 6 months and a repeat CT scan showed complete disappearance of the mass lesion and resolution of symptoms. Key Words: Tuberculosis, Pancreatic mass, Endoscopic ultrasound, Biopsy.

Experimental investigation and modelling of synergistic thermodynamic inhibition of Diethylene Glycol and glycine mixture on CO2 gas hydrates.

In this experimental and modelling study, Diethylene glycol (DEG) and Glycine (Gly) mixtures are introduced to hinder carbon dioxide hydrate formation by pushing the phase boundaries on the lower temperature side. The mixture of DEG and Gly with the ratio of 1:1 is experimented at 15, 10, and 5 wt% concentrations and the pressure vary from 2.5 to 4.0 MPa. The T-cycle method is employed to assess the effect of the studied blends on the CO2 hydrate by evaluating the hydrate dissociation temperature. Varied compositions of pure DEG and Gly as well as their mixtures are used to compute the synergistic effect. The studied system's thermodynamic hydrate inhibition (THI) influence is a concentration-driven phenomenon. Higher concentration can shift the hydrate liquid vapor equilibrium (HLVE) curve to lower temperatures and high-pressure regions. The outcomes depict that mixture of DEG and Gly at 15 wt%. Shows comparatively better results than the mixtures at 5 and 10 wt%, respectively. The obtained 10 wt% mixture results have also been compared with the conventional hydrate inhibitors and other THIs systems and provide a significant hydrate average suppression (ΔT) of 2.4 K. Furthermore, the freezing point-based Dickens and Quint Hunt model was also applied to predict the HLVE data of CO2 hydrates and satisfactory agreement found with maximum mean absolute error (MAE) of 0.498 K. A better inhibitory performance was seen when diethylene glycol and glycine were combined, demonstrating the potential of amino acids as synergistic inhibitors in the exploitation of hydrates, transportation of oil and gas, and flow assurance.

PI3K/AKT/mTOR Pathway-Associated Genes Reveal a Putative Prognostic Signature Correlated with Immune Infiltration in Hepatocellular Carcinoma.

Background: The dysregulated PI3K/AKT/mTOR pathway acts as the main regulator of tumorigenesis in hepatocellular carcinoma (HCC). Aim: Here, we identify the prognostic significance of PI3K/AKT/mTOR pathway-associated genes (PAGs) as well as their putative signature based on PAGs in an HCC patient's cohort. Methods: The transcriptomic data and clinical feature sets were queried to extract the putative prognostic signature. Results: We identified nine PAGs with different expressions. GO and KEGG indicated that these differentially expressed genes were associated with various carcinogenic pathways. Based on the signature-computed median risk score, we categorized the patients into groups of low risk and high risk. The survival time for the low-risk group is longer than that of the high-risk group in Kaplan-Meier (KM) curves. The prognostic value of risk score (ROC = 0.736) of receiver operating characteristic (ROC) curves performed better in comparison to that of other clinicopathological features. In both the GEO database and ICGC database, these outcomes were verified. The predictions of the overall survival rates in HCC patients of 1 year, 3 years, and 5 years can be obtained separately from the nomogram. The risk score was associated with the immune infiltrations of CD8 T cells, activated CD4 memory T cells, and follicular helper T cells, and the expression of immune checkpoints (PD-1, TIGIT, TIM-3, BTLA, LAG-3, and CTLA4) was positively relevant to the risk score. The sensitivity to several chemotherapeutic drugs can also be revealed by the signature. CDK1, PITX2, PRKAA2, and SFN were all upregulated in the tumor tissue of clinical samples. Conclusion: A putative and differential dataset-validated prognostic signature on the basis of integrated bioinformatic analysis was established in our study, providing the immunotherapeutic targets as well as the personalized treatment in HCC with neoteric insight.

Systematic molecular analysis of the human secretome and membrane proteome in gastrointestinal adenocarcinomas.

The human secretome and membrane proteome are a large source of cancer biomarkers. Membrane-bound and secreted proteins are promising targets for many clinically approved drugs, including for the treatment of tumours. Here, we report a deep systematic analysis of 957 adenocarcinomas of the oesophagus, stomach, colon and rectum to examine the cancer-associated human secretome and membrane proteome of gastrointestinal tract adenocarcinomas (GIACs). Transcriptomic data from these GIACs were applied to an innovative majority decision-based algorithm. We quantified significantly expressed protein-coding genes. Interestingly, we found a consistent pattern in a small group of genes found to be overexpressed in GIACs, which were associated with a cytokine-cytokine interaction pathway (CCRI) in all four cancer subtypes. These CCRI associated genes, which spanned both one secretory and one membrane isoform were further analysed, revealing a putative biomarker, interleukin-1 receptor accessory protein (IL1RAP), which indicated a poor overall survival, a positive correlation with cancer stemness and a negative correlation with several kinds of T cells. These results were further validated in vitro through the knockdown of IL1RAP in two human gastric carcinoma cell lines, which resulted in a reduced indication of cellular proliferation, migration and markers of invasiveness. Following IL1RAP silencing, RNA seq results showed a consistent pattern of inhibition related to CCRI, proliferation pathways and low infiltration of regulatory T cells (Tregs) and CD8 naive cells. The significance of the human secretome and membrane proteome is elucidated by these findings, which indicate IL1RAP as a potential candidate biomarker for cytokine-mediated cancer immunotherapy in gastric carcinoma.

INHBA is a novel mediator regulating cellular senescence and immune evasion in colorectal cancer.

Colorectal cancer (CRC) is one of the most mortal cancers in the world. Multiple factors and bio-processes are associated with in tumorigenesis and metastasis of CRC, including cellular senescence and immune evasion. This study aims to identify prognostic and immune-meditating effects of INHBA in CRC. Microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database to screen the differentially expressed genes (DEGs) in senescent cells and CRC tissues from the Cancer Genome Atlas (TCGA). Key factor was settled from the alternative DEGs set. Enrichment analyses and functional networks prediction were determined from online databases. Correlation analyses were performed to reveal the association among key factor, immune infiltration, T cell biomarkers and immune checkpoints. Moreover, expressions of key factors and immune checkpoints of tissue and blood samples from CRC patients as well as human CRC cell lines were measured. Results showed that Inhibin beta A (INHBA) was sorted out as a senescence-related factor and a prognostic predictor in CRC. What's more, INHBA was found highly co-expressed with T-cell biomarkers and immune checkpoints. In conclusion, INHBA was considered as a senescence-related regulator and a prognostic predictor in CRC, which also mediating immune evasion.

It's a Trap: A Case of Strangulated Coronary Guidewire and Longitudinal Stent Deformation in the Right Coronary Artery.

BACKGROUND Strangulation of the coronary guidewire is an infrequent complication of percutaneous coronary intervention (PCI), and it can lead to disastrous outcomes of stent thrombosis, vessel occlusion, and vessel damage. CASE REPORT Early-generation stents were made from stainless steel and had a bulky design as compared to cobalt-chromium or platinum chromium alloys, which have superior trackability at the cost of a thin core and low-strength struts, resulting in increased incidence of longitudinal stent deformation. We present a case of a 62-year-old active smoker with effort angina of Canadian Cardiovascular Society (CCS) class III. His coronary angiogram revealed a totally occluded right coronary artery (RCA). After placing 2 coronary guidewires (Run-through and Balanced middle-weight), Xience Xpedition (3.25×48 mm) and Promus Element (2.75×32 mm) were deployed through the whole length of the RCA. While placing the distal stent, the guidewire securing the posterior left ventricular (PLV) was trapped between 2 stents and all attempted maneuvers were unsuccessful in retrieving the wire. The stents sustained longitudinal deformation by the guide catheter, and subsequent arteriotomy for stent and wire retrieval and coronary artery bypass graft surgery were (CABG) performed. CONCLUSIONS Despite the remarkable safety profiles of the percutaneous equipment, complications still occur even with experienced operators. Calcified and tortuous vessels are primarily at risk for wire strangulation between stents or side-branches, and better deliverability of newer drug-eluting stents (DES) comes at the cost of reduced longitudinal strength.

Optical coherence tomography: assessment of coronary artery disease and guide to percutaneous coronary intervention.

BACKGROUND AND AIMS: Angiographic guidance for percutaneous coronary intervention (PCI) has significant limitations in interpretation. The superior spatial resolution of optical coherence tomography (OCT) can provide meaningful clinical benefits, although limited data is available on Asian populations. This study aimed to determine whether OCT can provide additional advantages and useful clinical information beyond that obtained by angiography alone in decision making for PCI. METHODS: This was an observational study based on a single tertiary cardiac center in Pakistan, which includes 67 patients who underwent coronary angiogram and stenting. Their pre and post stenting OCT findings were recorded. Any additional intervention was also recorded. The data were analysed using IBM SPSS software version 26.0. RESULTS: The mean age was 55.00 ± 9.00 years. Majority of the patients were males (65.7%). On angiography, there was an equal number of stable and ruptured plaques (38.8%). Post stenting results showed 29.9% under deployed stents and 34.3% were either undersized or mal-apposed. Out of 67 patients, 50 (74.6%) needed re-intervention after PCI. Among different procedures, post-dilatation was most common. CONCLUSION: The main OCT benefit is in borderline lesions on CA, in whom OCT identifies significant coronary stenosis and leads to PCI indication in patients. In the post-PCI context, OCT leads to an indication of PCI optimisation in half of the coronary lesions.

Myocardial blush grade: a determinant of left ventricular ejection fraction and adverse outcomes in STEMI.

BACKGROUND AND AIMS: Despite restoration of blood flow, subtle microvascular obstruction can occur. This obstruction can be graded using myocardial blush grade. We aimed to investigate the role of myocardial blush grade in ejection fraction and adverse outcomes, after percutaneous intervention. METHODS: A prospective, observational study was conducted at our institute with a calculated sample size. Variables such as age, gender, and ejection fraction were noted before the intervention. The patients were followed for 3 months to determine the outcomes. The data was analyzed using IBM SPSS software version 26.0. P-value of less than 0.05 was considered significant for the statistical tests. RESULTS: There were 74 male and 36 female participants in the study. The mean age was 52.20 ± 10.02 years. The most common adverse outcome was heart failure (18%). There was a significant Pearson's correlation between myocardial blush grade and improvement in ejection fraction (p < 0.05). Improvement in myocardial blush grade was significantly related to a decrease in adverse outcomes (p < 0.05). Regression analysis proved myocardial blush grade and diabetes status as independent predictors of percentage increase in ejection fraction (p < 0.05). CONCLUSION: High myocardial blush grade is one of the independent predictors of better outcomes in ST-elevation myocardial infarction.

Identification of Human Secretome and Membrane Proteome-Based Cancer Biomarkers Utilizing Bioinformatics.

Cellular secreted proteins (secretome), together with cellular membrane proteins, collectively referred to as secretory and membrane proteins (SMPs) are a large potential source of biomarkers as they can be used to indicate cell types and conditions. SMPs have been shown to be ideal candidates for several clinically approved drug regimens including for cancer. This study aimed at performing a functional analysis of SMPs within different cancer subtypes to provide great clinical targets for potential prognostic, diagnostic and the therapeutics use. Using an innovative majority decision-based algorithm and transcriptomic data spanning 5 cancer types and over 3000 samples, we quantified the relative difference in SMPs gene expression compared to normal adjacent tissue. A detailed deep data mining analysis revealed a consistent group of downregulated SMP isoforms, enriched in hematopoietic cell lineages (HCL), in multiple cancer types. HCL-associated genes were frequently downregulated in successive cancer stages and high expression was associated with good patient prognosis. In addition, we suggest a potential mechanism by which cancer cells suppress HCL signaling by reducing the expression of immune-related genes. Our data identified potential biomarkers for the cancer immunotherapy. We conclude that our approach may be applicable for the delineation of other types of cancer and illuminate specific targets for therapeutics and diagnostics.

IL1R2 Blockade Suppresses Breast Tumorigenesis and Progression by Impairing USP15-Dependent BMI1 Stability.

Breast tumor initiating cells (BTICs) with ALDH+CD24-CD44+ phenotype are the most tumorigenic and invasive cell population in breast cancer. However, the molecular mechanisms are still unclear. Here, it is found that a negative immune regulator interleukin-1 receptor type 2 (IL1R2) is upregulated in breast cancer (BC) tissues and especially in BTICs. BC patients with high IL1R2 expression have a poorer overall survival and relapse-free survival. High IL1R2 promotes BTIC self-renewal and BC cell proliferation and invasion. Mechanistically, IL1R2 is activated by IL1ß, as demonstrated by the fact that IL1ß induces the release of IL1R2 intracellular domain (icd-IL1R2) and icd-IL1R2 then interacts with the deubiquitinase USP15 at the UBL2 domain and promotes its activity, which finally induces BMI1 deubiquitination at lysine 81 and stabilizes BMI1 protein. In addition, IL1R2 neutralizing antibody can suppress the protein expression of both IL1R2 and BMI1, and significantly abrogates the promoting effect of IL1R2 on BTIC self-renewal and BC cell growth both in vitro and in vivo. The current results indicate that blocking IL1R2 with neutralizing antibody provides a therapeutic approach to inhibit BC progression by targeting BTICs.

A Single Coronary Artery with an Absent Right Coronary and a Superdominant Left Circumflex Giving off a Branch Supplying the Right Coronary Artery Territory.

An absent right coronary artery (RCA) with single left coronary artery (LCA) originating from left aortic sinus with a superdominant left circumflex (LCX) and giving off an RCA branch is one of the rarest coronary artery anomalies. It occurs with an incidence of less than 0.1%. Usually, patients are asymptomatic and abnormality is found incidentally on cardiac catheterisation or CT angiography. We present a case report of an unusual coronary anomaly in a patient who presented with anterior myocardial infarction. Patient was subjected to coronary angiography, which revealed absent RCA originating from distal LCX artery, supplying the base of heart and RCA territory. He underwent primary percutaneous intervention (PCI) with stenting to the left anterior descending (LAD) artery. This type of anomaly, in which single LCA from which dominant LCX continues as RCA, is important to diagnose and manage if diseased, as stenosis of the dominant LCX artery in such cases can jeopardise a large portion of myocardium, which can lead to increased morbidity and mortality, if left untreated.

Optical Coherence Tomography-guided Intervention in STEMI Patients with Normal Looking Coronaries.

Optical coherence tomography (OCT) is an increasingly available intracoronary imaging modality that provides highresolution imaging of coronary arteries and guides operators in percutaneous coronary intervention (PCI) by accurately defining luminal geometry and detailed plaque composition. The two cases under discussion in this report, presented with acute ST elevation myocardial infarction (STEMI) with angiography showing minor narrowing (<30%) with TIMI III flow in which OCT-guided approach was used regarding the management owing to its improved temporal and axial resolution, thus providing proper plaque assessment and subsequent proper management.