Liquid Biopsy in Hepatocellular Carcinoma: Opportunities and Challenges for Immunotherapy

Hepatocellular carcinoma (HCC) is one of the deadliest cancer types worldwide. HCC is often diagnosed at a late stage when the therapeutic options are very limited. However, even at the earlier stages, the best treatment is liver transplantation, surgical resection or ablation. Surgical resection and ablation may carry a high risk of tumor recurrence. The recent introduction of immunotherapies resulted in clinical responses for a subgroup of patients, but there were still no effective predictive markers for response to immunotherapy or for recurrence after surgical therapy. The identification of biomarkers that could correlate and predict response or recurrence would require close monitoring of the patients throughout and after the completion of treatment. However, this would not be performed efficiently by repeated and invasive tissue biopsies. A better approach would be to use liquid biopsies including circulating tumor DNA (ctDNA), circulating RNA (e.g., microRNAs), circulating tumor cells (CTC) and extracellular vesicles (EVs) (e.g., exosomes) for disease monitoring in a non-invasive manner. In this review, we discuss the currently available technology that can enable the use of liquid biopsy as a diagnostic and prognostic tool. Moreover, we discuss the opportunities and challenges of the clinical application of liquid biopsy for immunotherapy of HCC.

RNA-based gene therapy for manipulating the neuroinflammatory cascade closely linked to neurodegeneration can help reduce disease development

RNA-based medicine, such as miRNA and aptamers-based biopharmaceuticals, is a relatively new therapeutic class with great promise to cure and prevent chronic and rare diseases. miRNAs are both a target and a therapeutic molecule in their early stages, and every shred of evidence supplied by RNA-based research has indicated future potential. AntagomiRs, sponges, and circular RNA are examples of miRNAs as mimetics or inhibitors. miRNAs may be found in blood plasma, serum, and CSF as intracellular and extracellular circulating RNA, making them useful as diagnostic and prognostic biomarkers in many NDDs. Currently, there are no treatments for these illnesses, mostly due to their late detection. Controlling the neuroinflammatory cascade closely connected to neurodegeneration can help prevent the progression of the condition. Since miRNAs may influence a single gene, as well as all cellular pathways and associated activities, restoring or enhancing their expression is one of the most challenging problems to employ as a therapeutic strategy. However, RNA aptamers act directly by interacting with cellular receptors when therapeutically appropriate oligonucleotides are given. As a diagnostic marker, it has a wide range of functions. Because it operates swiftly by interacting with the target, the aptamer creates substantial difficulty with site-specific targeted delivery. It is also an effective, targeted miRNA delivery agent. Aptamers are less costly to produce, non-immunogenic and thermostable compared to other RNA-based medicines. NDDs have long been difficult to detect and treat, and we still don't know all about them. In the near future, further RNA-based medications may be expected to achieve recognition in the diagnostic and therapeutic areas of NDD, with higher drug potency, decreased toxicity and immunogenicity compared to traditional medication.

Circulating RNA in Kidney Cancer: What We Know and What We Still Suppose

Renal cancer represents the 7th most common tumor worldwide, affecting 400,000 people annually. This malignancy, which is the third most frequent cancer among urological diseases, displays a completely different prognosis if the tumor is detected in the early stages or advance phases. Unfortunately, more than 50% of renal cancers are discovered incidentally, with a consistent percentage of cases where the tumor remains clinically silent till the metastatic process is established. In day-to-day clinical practice, no available predictive biomarkers exist, and the existent imaging diagnostic techniques harbor several gaps in terms of diagnosis and prognosis. In the last decade, many efforts have been reported to detect new predictive molecular biomarkers using liquid biopsies, which are less invasive in comparison to renal biopsy. However, until now, there has been no clear evidence that a liquid biopsy biomarker could be relevant to the creation of a precise and tailored medical management in these oncological patients, even though circulating RNA biomarkers remain among the most promising. Given the idea that liquid biopsies will play a future key role in the management of these patients, in the present review, we summarize the current state of circulating RNA (miRNA, lncRNAs, and circRNAs) as possible biomarkers of renal cancer presence and aggressiveness in patients.

Circulating RNA biomarkers in diffuse large B-cell lymphoma: a systematic review

Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype of non-Hodgkin’s lymphomas (NHL). DLBCL is an aggressive malignancy that displays a great heterogeneity in terms of morphology, genetics and biological behavior. While a sustained complete remission is obtained in the majority of patients with standard immunochemotherapy, patients with refractory of relapsed disease after first-line treatment have a poor prognosis. This patient group represents an important unmet need in lymphoma treatment. In recent years, improved understanding of the underlying molecular pathogenesis had led to new classification and prognostication tools, including the development of cell-free biomarkers in liquid biopsies. Although the majority of studies have focused on the use of cell-free fragments of DNA (cfDNA), there has been an increased interest in circulating-free coding and non-coding RNA, including messenger RNA (mRNA), microRNA (miRNA), long non-coding RNA (lncRNA) and circular RNA (circRNA), as well as RNA encapsulated in extracellular vesicles or tumor-educated platelets (TEPs). We performed a systematic search in PubMed to identify articles that evaluated circulating RNA as diagnostic, subtype, treatment response or prognostic biomarkers in a human DLBCL population. A total of 35 articles met the inclusion criteria. The aim of this systematic review is to present the current understanding of circulating RNA molecules as biomarker in DLBCL and to discuss their future potential.

Serum microRNA Levels in Diabetes Mellitus

The aim of our study is to evaluate the serum circulating levels of some miRNA, such as hsa-let-7b-5p, hsa-let-7a-5p, hsa-miR-320b, hsa-miR-23a-3p, hsa-miR-27a-3p, hsa-miR-15a-5p, and hsa-miR-495-3, in diabetic patients without diabetic retinopathy (DR), diabetic patients with DR, and, healthy subjects in order to find reliable and reproducible biomarkers for DR. A total of 45 subjects underwent serum sampling for miRNAs evaluation and a complete ophthalmologic examination, including microperimetry and widefield swept source optical coherence tomography angiography (OCTA). Total circulating RNA was isolated from patients using the miRNeasy Serum/Plasma Kit. Serum miRNA expression levels were significantly different in the three groups. In detail, circulating hsa-miR-15a-5p levels were significantly reduced in both diabetic patients without DR and diabetic patients with DR (p = 0.027). Serum hsa-miR-495-3p was lower in diabetic patients with DR and diabetic patients without DR (p = 0.049). Hsa-miR-23a-3p serum expression levels were significantly lower in diabetic patients with DR and diabetic patients without DR (p = 0.013). Significant associations of miRNAs with anatomical/perfusion parameters and functional parameters were observed in the diabetic groups. We find evidence of damage in progression biomarkers in DR that are evidently early in patients with diabetes without DR. Serum miRNAs levels are considered to have strong potential as a novel biomarker for the early detection of DR in subjects suffering from diabetes and could represent noninvasive target therapies to block the progression of the disease at the early stages.

Data Resource Profile: thousands of circulating RNA profiles of pre-clinical samples from the Janus Serum Bank Cohort

There is justified optimism regarding the use of miRNAs as early detection biomarkers of cancer. They are well characterized and are involved in all the hallmarks of cancer. Less is known about the role of most other non-coding RNA (ncRNAs) classes in normal physiology and tumorigenesis. The JanusRNA dataset consist of circulating RNA profiles of pre-clinical samples from 1631 cancer patients and 673 cancer-free controls. We studied eight cancer types including cancer of the: lung, colon, rectum, prostate, breast, testis, ovaries and gallbladder. JanusRNA has its origin from the large population-based Janus Serum Bank Cohort which consists of 318 628 Norwegians. The dataset combines information from the complete nationwide cancer registry, RNA sequencing profiles from 1631 cancer patients and 673 cancer-free controls, as well as data on lifestyle, anthropometry and biochemical measurements from national health surveys. The Janus Serum Bank is specifically suited for studies of early detection and risk biomarkers of cancer, since samples are collected nationwide over a large time span, pre-clinically and cancer occurs at different points in time after blood draw. We used a nested case-control design, selecting both cases and controls among the Janus cohort members. We restricted our selection to cases with at least one sample collected within 10 years prior to cancer diagnosis. We selected 673 cancer-free Janus participants for comparison of RNA levels with the cancer cases. The controls were frequency matched to the case group on sex, age at blood donation and date of blood donation. The JanusRNA dataset has been used to investigate the natural variation of circulating RNAs in cancer-free individuals. This data resource was also used in a study of variation in RNA expression associated with common traits like age, sex, smoking, BMI and physical activity in cancer-free individuals. RNA dynamics in lung and testicular carcinogenesis throughout a 10-year follow-up has also been studied.

Investigating Pregnancy and Its Complications Using Circulating Cell-Free RNA in Women's Blood During Gestation

In recent years, there have been major advances in the application of non-invasive techniques to predict pregnancy-related complications, for example by measuring cell-free RNA (cfRNA) in maternal blood. In contrast to cell-free DNA (cfDNA), which is already in clinical use to diagnose fetal aneuploidy, circulating RNA levels can correspond with tissue-specific gene expression and provide a snapshot of prenatal health across gestation. Here, we review the physiologic origins of cfRNA and its novel applications and corresponding challenges to monitor fetal and maternal health and predict pregnancy-related complications.