Clinical and Experimental Medicine最新文献

Hemophilia A (HA) patients under emicizumab prophylaxis may require the concomitant use of procoagulant factors for breakthrough bleedings or immune tolerance induction (ITI). The aim of this study is to evaluate the ex vivo procoagulant effect of plasma-derived FVIII concentrates containing von Willebrand factor (pdFVIII/VWF) in samples from patients with severe HA without inhibitors on emicizumab prophylaxis. Samples from healthy controls (HC) and HA patients were drawn in sodium citrate plus corn trypsin inhibitor tubes and spiked with increasing concentrations of pdFVIII/VWF concentrates (10-400 IU/dL) (Fanhdi^®/Alphanate^®, Grifols), activated prothrombin complex concentrate (aPCC, 0.5 U/mL) or recombinant activated factor VII (rFVIIa, 0.9 µg/mL). Global coagulation was measured by rotational thromboelastometry (ROTEM) (clotting time [CT] and time to maximum clot formation velocity [MAXV-t]) and thrombin generation (TG) assay (thrombin peak [TP] and endogenous thrombin potential [ETP]). Samples from HA patients under emicizumab prophylaxis showed CT and MAXV-t values above HC levels, while TP and ETP were below HC levels. Ex vivo pdFVIII/VWF supplementation increased TP and ETP and shortened CT and MAXV-t dose-dependently. At 50 IU/dL (≈25 IU/kg), pdFVIII/VWF normalized clot formation and restored TG within HC normal range. The highest pdFVIII/VWF concentration (400 IU/dL) and rFVIIa did not result in an excessive procoagulant profile. However, aPCC induced ex vivo an excessive TG and markedly decreased ROTEM parameters (CT and MAXV-t). Coagulation parameters of both methods significantly correlated at baseline and with increasing concentrations of pdFVIII/VWF. High doses of pdFVIII/VWF concentrates, similar to those used for ITI, did not trigger a multiplying procoagulant effect to samples from HA patients on emicizumab prophylaxis, evidencing their low thrombotic risk in these patients.

This study aims to comprehensively analyze the role of the exportin (XPO) family in the development and progression of cancer. These nuclear transport proteins have been increasingly recognized for their involvement in oncogenic processes and tumor growth. We utilized updated public databases and bioinformatics tools to assess the expression levels of the XPO family and their associations with key oncological markers including patient survival, immune subtypes, tumor microenvironment, stemness scores, drug sensitivity, and DNA methylation across various cancers. Expression levels of XPO family proteins varied significantly across different cancer types, indicating cancer-specific roles. Specific XPO proteins were linked to adverse prognosis in particular cancers. Additionally, expression levels were correlated with classifications of immune subtypes and tumor purity; notably, lower expression levels were often found in tumors with elevated stromal and immune scores. A marked correlation was observed between XPO proteins and RNA stemness scores, whereas the correlation with DNA stemness scores varied. Furthermore, XPO expression levels significantly influenced cancer cell drug sensitivity and generally showed correlations with gene methylation patterns, although these correlations differed among cancer types. Our findings underscore the distinct roles of XPO family members in cancer, linking them to immune infiltration, the tumor microenvironment, and drug sensitivity. These insights not only enhance our understanding of the prognostic and therapeutic potentials of XPO proteins in cancer but also lay the groundwork for further studies into their mechanisms and applications in cancer diagnosis and treatment.

Pancreatic cancer (PC) is a malignancy of the gastrointestinal tract that is characterized by a poor prognosis. This study investigates the roles of immunogenic cell death (ICD) genes in the prognosis and progression of PC. Expression data for PC patients were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, while ICD genes were sourced from published literature. We explored the expression patterns and identified two distinct clusters based on ICD genes. Kaplan-Meier analysis, differential expression analysis, tumor mutational burden analysis, and immune cell infiltration analysis were performed on these clusters. An ICD gene-based risk model was developed, categorizing samples from the TCGA and GEO datasets into low- and high-risk groups. Additionally, we investigated the expression levels of the genes included in the risk model within the TCGA cohort and our own samples. Finally, a loss-of-function assay was conducted to assess the role of MYD88 in PC. Two clusters of PC samples were identified, patients in the ICD-low cluster exhibited a higher degree of immune cell enrichment. The survival time of patients in the low-risk group was longer than that of those in the high-risk group. The genes included in the risk model (CASP1, MYD88, and PIK3CA) showed upregulated expression levels in tumor samples. Furthermore, the predictive accuracy of our risk model was validated using our own samples. Genetic inhibition of MYD88 led to significantly decreased proliferation and migration of PC cells in the loss-of-function assay. There were disparities in survival time and tumor immune microenvironment (TIME) between two ICD gene clusters. Additionally, we developed an ICD-related risk model that was validated as an independent prognostic indicator for patients with PC.

In recent years, the incidence of ground-glass nodular lung adenocarcinoma has gradually increased. Preoperative evaluation of the tumor invasiveness is very important, but there is a lack of effective methods. Plasma samples of ground-glass nodular lung adenocarcinoma and healthy volunteers were collected. Pulmonary nodules with different densities were compared by metabolomics. Different invasive degrees of lung adenocarcinoma were contrasted as well. Multivariate statistical methods were applied to search for significant metabolites from comparisons between two groups. The common metabolites among the different comparisons were selected and then assessed by various indices. Five metabolites were discovered for lung adenocarcinoma with different invasive degrees. Significant metabolites were selected for pulmonary nodules with different densities as well. When these metabolites were cross-compared, only the level of lysoPC(18:3) was significantly lower in ground-glass nodular lung adenocarcinoma than healthy population, as opposed to other metabolites. After identifying the invasive degree of pulmonary ground-glass nodules, lysoPC(18:3) showed a satisfactory sensitivity and specificity, both greater than 0.85. Metabolomics analysis has favorable advantages in the study of ground-glass nodular lung adenocarcinoma. LysoPC(18:3) may have the potential to differentiate precancerous lesions from invasive lung cancer, which could help clinicians to make proper judgment before surgery.

Human hepatocellular carcinoma (HCC) has been identified as a significant cause of mortality worldwide. In recent years, extensive research has been conducted to understand the underlying mechanisms of autophagy in the pathogenesis of the disease, with the aim of developing novel therapeutic agents. Targeting autophagy with conventional therapies in invasive HCC has opened up new opportunities for treatment. However, the emergence of resistance and the immunosuppressive tumor environment highlight the need for combination therapy or specific targeting, as well as an efficient drug delivery system to ensure targeted tumor areas receive sufficient doses without affecting normal cells or tissues. In this review, we discuss the findings of several studies that have explored autophagy as a potential therapeutic approach in HCC. We also outline the potential and limitations of standard therapies for autophagy modulation in HCC treatment. Additionally, we discuss how different combination therapies, nano-targeted strategies, and oncolytic virotherapy could enhance autophagy-based HCC treatment in future research.

Immunotherapy has changed the treatment landscape of cancer in the past decade. Amongst various forms of immunotherapy, manipulating the T cell has shown promise in past few years. T cell manipulation can be done by CAR-T cell therapy or bispecific antibodies. These 2 therapeutic modalities have been studied and shown efficacy in hematologic malignancies in relapsed refractory setting. They have not been compared to each other in randomized control trials; hence, the adequate sequencing is not known. Although cross-trial comparison is not ideal, available evidence indicates toward similar efficacy and better tolerability of BiTEs compared to CAR-T cell therapy. Bispecific antibodies, though, have an advantage of being able to be used in an "off the shelf" manner considering these are not MHC specific and can be administered to all patients regardless of HLA type. There has been an explosive growth in the indications for bispecific antibodies in the recent past. In this article, we have reviewed recent approvals, indication and literature regarding efficacy and adverse effects of bispecific antibodies in all available indications. This will be a useful read for clinical practitioners to understand the mechanism of action and place of all available bispecific antibodies in the current oncology landscape.

The term "microbiome" refers to the collection of bacterial species that reside in the human body's tissues. Sometimes, it is used to refer to all microbial entities (bacteria, viruses, fungi, and others) which colonize the human body. It is now generally acknowledged that the microbiome plays a critical role in the host's physiological processes and general well-being. Changes in the structure and/or function of the microbiome (dysbiosis) are linked to the development of many diseases including cancer. The claim that because of their negatively charged membrane, cancer cells are more vulnerable to some bacteria than normal cells and that is how the link between these bacteria and cancer evolved has been refuted. Furthermore, the relationship between the microbiome and cancer is more evident in the emerging field of cancer immunotherapy. In this narrative review, we detailed the correlation between the presence/absence of specific bacterial species and the development, diagnosis, prognosis, and treatment of some types of cancer including colorectal, lung, breast, and prostate cancer. In addition, we discussed the mechanisms of microbiome-cancer interactions including genotoxin production, the role of free radicals, modification of signaling pathways in host cells, immune modulation, and modulation of drug metabolism by microbiome. Future directions and clinical application of microbiome in the early detection, prognosis, and treatment of cancer emphasizing on the role of fecal transplantation, probiotics, prebiotics, and microbiome biomarkers were also considered.

South Africa has a high burden of human immune deficiency virus (HIV)-associated Hodgkin lymphoma (HL) which is typically Epstein-Barr virus (EBV) infected, detected by histological stains. Circulating plasma EBV derived from apoptotic EBV infected tumour cells is a potential biomarker. This study aimed to evaluate the role of plasma EBV load testing in newly diagnosed HL patients and correlate pretreatment plasma EBV levels, HIV status and EBV tumour status with overall survival (OS). Untreated HL patients were prospectively included. Polymerase chain reaction measured EBV plasma viral loads. Kaplan-Meier curves with log-rank tests estimated the impact of HIV, EBV tumour status and plasma EBV viral loads on OS. Multivariable analysis was performed using a Cox proportional hazards model. Receiver operative characteristic curve analysis determined cutoff plasma EBV DNA levels with optimal sensitivity, specificity and concordance with tumour EBV status. The 68 patients included 21 (31%) HIV +ve and 33 (49%) EBV tumour +ve. EBV plasma ≥ 10 000 IU/ml (P = 0.008), EBV +ve tumour (P = 0.014), HIV +ve status (P = 0.009) and age ≥ 45 years (P = 0.018) predicted poorer OS on univariate analysis. Plasma EBV levels > 762 IU/ml had 89.29% sensitivity and 96.77% specificity for detecting EBV +ve HL. High plasma EBV levels ≥ 10 000 IU/ml, HIV +ve status and EBV tumour +ve status predicted poorer OS. Plasma EBV levels > 762 IU/ml predicted EBV +ve tumour status with high sensitivity and specificity. Plasma EBV viral DNA testing is a promising biomarker for EBV +ve HL.

Hypoxia is one of the main hallmarks of hepatocellular carcinoma (HCC) resulting from improper oxygenation and insufficient nourishment of the HCC microenvironment. The effect of hypoxia is mediated by hypoxia-inducible factor-1A (HIF-1A) via targeting various downstream pathways, including glycolysis, angiogenesis, and survival signaling. However, HCC cell lines in a 2-dimensional (2D) setting do not resemble the metabolic signature of HCC. Here we aim to overcome these limitations by developing an HCC organoid that recapitulates the HIF-1A metabolic shift. The enrichment analysis of the RNA-Seq data revealed that HIF-1A-driven glycolytic shift is of the significant pathways. The established organoid model, using xeno-free plasma-derived extracellular matrix (ECM) as a scaffold and nutritive biomatrix, maintained its structural integrity and viability for up to 14 days; the comparative analysis of the cobalt (II) chloride (CoCl₂)-treated organoids to the untreated ones unveiled reduced size and proliferative capacity. Interestingly, our organoid model showed an elevated expression of HIF-1A and glycolysis enzymes compared to their counterparts in the CoCl₂-treated organoids. HIF-1A molecular expression-translated biochemical signature is further assessed in our spontaneously growing organoids showing an increase in glucose uptake, intracellular pyruvate, extracellular lactate dehydrogenase expression, and extracellular lactate production, while hydrogen peroxide (H₂O₂), a marker for oxidative metabolism, is reduced. Our data confirmed the potency of the established organoid model to mimic the molecular and biochemical HIF-1A-driven metabolism, which validates its potential use as an in vitro HCC model. Our model naturally simulates hypoxic conditions and simultaneous HIF-1A-dependent glycolysis within HCC rather than using of CoCl₂-induced hypoxic conditions.

Clear cell renal cell carcinoma (ccRCC), a predominant form of urinary malignancy, requires the identification of reliable biomarkers to enhance both prognostic outcomes and therapeutic developments specific to ccRCC. NSUN5, a member of the NOL1/NOP2/SUN domain (NSUN) family, plays a critical role in RNA stabilization and exhibits widespread expression across various tumor types. However, the exact function of NSUN5 in ccRCC remains insufficiently understood. Data were collated from cohorts of ccRCC patients who underwent nephrectomy, including those from the Cancer Genome Atlas (TCGA) and the Sun Yat-sen University Cancer Center (SYSUCC), to evaluate the clinical relevance of NSUN5. Integrative models based on NSUN5 expression were subsequently developed to predict the prognosis of ccRCC within the TCGA and SYSUCC cohorts. Furthermore, the impact of NSUN5 on RCC cells and its association with cellular senescence were corroborated through in vitro experimental analyses. NSUN5 exhibited elevated expression in both ccRCC patients and renal cancer cell lines, whose upregulation significantly correlated with age, tumor size, TNM stage, WHO/International Society of Urological Pathology (ISUP) grade, presence of necrosis, and a poor prognosis. An accessible nomogram, incorporating NSUN5 along with various clinicopathological parameters, was adept at predicting outcomes for ccRCC patients. Additionally, in vitro findings indicated that reduced expression of NSUN5 enhanced tumor cell senescence and simultaneously inhibiting cell proliferation and migration. These observations suggest that elevated NSUN5 expression is linked to poorer overall survival (OS) and progression-free survival (PFS), positioning NSUN5 as a viable diagnostic and prognostic biomarker in ccRCC.