LncRNAs and the Angiogenic Switch in Cancer: Clinical Significance and Therapeutic Opportunities

Angiogenesis is one of the hallmarks of cancer, and the establishment of new blood vessels is vital to allow for a tumour to grow beyond 1–2 mm in size. The angiogenic switch is the term given to the point where the number or activity of the pro-angiogenic factors exceeds that of the anti-angiogenic factors, resulting in the angiogenic process proceeding, giving rise to new blood vessels accompanied by increased tumour growth, metastasis, and potential drug resistance. Long noncoding ribonucleic acids (lncRNAs) have been found to play a role in the angiogenic switch by regulating gene expression, transcription, translation, and post translation modification. In this regard they play both anti-angiogenic and pro-angiogenic roles. The expression levels of the pro-angiogenic lncRNAs have been found to correlate with patient survival. These lncRNAs are also potential drug targets for the development of therapies that will inhibit or modify tumour angiogenesis. Here we review the roles of lncRNAs in regulating the angiogenic switch. We cover specific examples of both pro and anti-angiogenic lncRNAs and discuss their potential use as both prognostic biomarkers and targets for the development of future therapies.

Patient Survival Between Hemodialysis and Peritoneal Dialysis Among End-Stage Renal Disease Patients Secondary to Myeloperoxidase-ANCA-Associated Vasculitis

BackgroundA significant proportion of anti-neutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis eventually progresses to end-stage renal disease (ESRD) thus requiring long-term dialysis. There is no consensus about which dialysis modality is more recommended for those patients with associated vasculitis (AAV-ESRD). The primary objective of this study was to compare patient survival in patients with AAV-ESRD treated with hemodialysis (HD) or peritoneal dialysis (PD).MethodsThis double-center retrospective cohort study included dialysis-dependent patients who were treated with HD or PD. Clinical data were collected under standard format. The Birmingham vasculitis activity score (BVAS) was used to evaluate disease activity at diagnosis and organ damage was assessed using the vasculitis damage index (VDI) at dialysis initiation.ResultsIn total, 85 patients were included: 64 with hemodialysis and 21 with peritoneal dialysis. The patients with AAV-PD were much younger than the AAV-HD patients (48 vs. 62, P < 0.01) and more were female (76.2 vs. 51.6%, P = 0.05). The laboratory data were almost similar. The comorbidities, VDI score, and immuno-suppressive therapy at dialysis initiation were almost no statistical difference. Patient survival rates between HD and PD at 1 year were 65.3 vs. 90% (P = 0.062), 3 year were 59.6 vs. 90% (P < 0.001), and 5 years were 59.6 vs. 67.5% (P = 0.569). The overall survival was no significant difference between the two groups (P = 0.086) and the dialysis modality (HD or PD) was not shown to be an independent predictor for all-cause death (hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.31–1.7; P = 0.473). Cardio-cerebrovascular events were the main cause of death among AAV-HD patients while infection in patients with AAV-PD.ConclusionThese results provide real-world data that the use of either hemodialysis or peritoneal dialysis modality does not affect patient survival for patients with AAV-ESRD who need long-term dialysis.

Therapeutic Potential of Naturally Occurring Small Molecules to Target the Wnt/β-Catenin Signaling Pathway in Colorectal Cancer

Colorectal cancer (CRC) ranks second in the number of cancer deaths worldwide, mainly due to late diagnoses, which restrict treatment in the potentially curable stages and decrease patient survival. The treatment of CRC involves surgery to remove the tumor tissue, in addition to radiotherapy and systemic chemotherapy sessions. However, almost half of patients are resistant to these treatments, especially in metastatic cases, where the 5-year survival rate is only 12%. This factor may be related to the intratumoral heterogeneity, tumor microenvironment (TME), and the presence of cancer stem cells (CSCs), which is impossible to resolve with the standard approaches currently available in clinical practice. CSCs are APC-deficient, and the search for alternative therapeutic agents such as small molecules from natural sources is a promising strategy, as these substances have several antitumor properties. Many of those interfere with the regulation of signaling pathways at the central core of CRC development, such as the Wnt/β-catenin, which plays a crucial role in the cell proliferation and stemness in the tumor. This review will discuss the use of naturally occurring small molecules inhibiting the Wnt/β-catenin pathway in experimental CRC models over the past decade, highlighting the molecular targets in the Wnt/β-catenin pathway and the mechanisms through which these molecules perform their antitumor activities.

CCT3-LINC00326 axis regulates hepatocarcinogenic lipid metabolism

ObjectiveTo better comprehend transcriptional phenotypes of cancer cells, we globally characterised RNA-binding proteins (RBPs) to identify altered RNAs, including long non-coding RNAs (lncRNAs).DesignTo unravel RBP-lncRNA interactions in cancer, we curated a list of ~2300 highly expressed RBPs in human cells, tested effects of RBPs and lncRNAs on patient survival in multiple cohorts, altered expression levels, integrated various sequencing, molecular and cell-based data.ResultsHigh expression of RBPs negatively affected patient survival in 21 cancer types, especially hepatocellular carcinoma (HCC). After knockdown of the top 10 upregulated RBPs and subsequent transcriptome analysis, we identified 88 differentially expressed lncRNAs, including 34 novel transcripts. CRISPRa-mediated overexpression of four lncRNAs had major effects on the HCC cell phenotype and transcriptome. Further investigation of four RBP-lncRNA pairs revealed involvement in distinct regulatory processes. The most noticeable RBP-lncRNA connection affected lipid metabolism, whereby the non-canonical RBP CCT3 regulated LINC00326 in a chaperonin-independent manner. Perturbation of the CCT3-LINC00326 regulatory network led to decreased lipid accumulation and increased lipid degradation in cellulo as well as diminished tumour growth in vivo.ConclusionsWe revealed that RBP gene expression is perturbed in HCC and identified that RBPs exerted additional functions beyond their tasks under normal physiological conditions, which can be stimulated or intensified via lncRNAs and affected tumour growth.

A Pan-Cancer Study of KMT2 Family as Therapeutic Targets in Cancer

Objective. Exome sequencing studies have shown that the histone-lysine N-methyltransferase 2 (KMT2) gene is one of the most commonly mutated genes in a range of human malignancies and is linked to some of the most common and deadly solid tumors. However, the connection between this gene family’s function and tumor type, immunological subtype, and molecular subtype dependency is still unknown. Methods. We examine the expression patterns of the histone-lysine N-methyltransferase 2 (KMT2) gene, as well as their relationship to patient survival. We also used a pan-cancer analysis to link their function to immunological subtypes, the tumor microenvironment, and treatment sensitivity. Results. Using the TCGA pan-cancer data, researchers looked at and examined KMT2 expression patterns and their links to patient survival and the tumor microenvironment in 33 cancer types. The expression of the KMT2 family changes significantly across and within cancer types, indicating significant inter- and intracancer heterogeneity. Patients’ overall survival was often linked to the expression of KMT2 family members. However, the direction of the link differed depending on the KMT2 isoform and cancer type studied. Notably, in all cancer types examined, nearly all KMT2 family members were substantially linked with overall survival in patients with renal clear cell carcinoma (KIRC). Furthermore, all KMT2 genes have a strong relationship with immune infiltrate subtypes, as well as varying degrees of stromal cell infiltration and tumor cell stemness. Finally, we discovered that higher expression of KMT2s, particularly KMT2F and KMT2G, was linked to greater chemotherapeutic sensitivity in several cell lines. Conclusions. The necessity to investigate each KMT2 member as a distinct entity inside each particular cancer type is highlighted by our comprehensive investigation of KMT2 gene expression and its relationship with immune infiltrates, tumor microenvironment, and cancer patient outcomes. Our research also confirmed the identification of KMT2 as a potential therapeutic target in cancer, but further laboratory testing is required.

Precision Cardio-Oncology: Use of Mechanistic Pharmacokinetic and Pharmacodynamic Modeling to Predict Cardiotoxicities of Anti-Cancer Drugs

The cardiotoxicity of anti-cancer drugs presents as a challenge to both clinicians and patients. Significant advances in cancer treatments have improved patient survival rates, but have also led to the chronic effects of anti-cancer therapies becoming more prominent. Additionally, it is difficult to clinically predict the occurrence of cardiovascular toxicities given that they can be transient or irreversible, with large between-subject variabilities. Further, cardiotoxicities present a range of different symptoms and pathophysiological mechanisms. These notwithstanding, mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) modeling offers an important approach to predict cardiotoxicities and offering precise cardio-oncological care. Efforts have been made to integrate the structures of physiological and pharmacological networks into PK-PD modeling to the end of predicting cardiotoxicities based on clinical evaluation as well as individual variabilities, such as protein expression, and physiological changes under different disease states. Thus, this review aims to report recent progress in the use of PK-PD modeling to predict cardiovascular toxicities, as well as its application in anti-cancer therapies.

obesity paradox and mortality after pathological hip fractures: a Swedish registry study

Background and purpose — Obesity as measured by BMI has been associated with increased survival in various diseases, a phenomenon known as the “obesity paradox.” It is unknown whether obesity is associated with survival after pathological fractures. We investigated the association between BMI and survival after surgery for pathological hip fracture, to improve survival prognostication, and lay grounds for further interventional nutritional studies. Patients and methods — We analyzed prospectively collected data from Swedish nationwide registry “RIKSHÖFT.” The study cohort included 1,000 patients operated for a pathological hip fracture between 2014 and 2019. BMI registered on admission was available in 449 patients. Overall patient survival was measured according to the Kaplan–Meier method. Multivariable regression was used to evaluate association with other potential factors that influence patient survival. Results — Overweight and obesity were associated with an increased postoperative survival in male patients with surgically treated pathological hip fractures. Multivariable analysis considering potential confounders confirmed this finding. The association was not that strong in women and did not reach statistical significance. Interpretation — BMI, a commonly available clinical parameter, is a good predictor of overall survival for patients operated on for pathological hip fracture. Incorporation of BMI in existent survival prognostication algorithms should be considered. Treatment of malnutrition in this frail group of patients is worth studying.

A viewpoint on material and design considerations for oesophageal stents with extended lifetime

Oesophageal stents are meshed tubular implants designed to maintain patency of the oesophageal lumen and attenuate the symptoms of oesophageal cancer. Oesophageal cancers account for one in twenty cancer diagnoses and can lead to dysphasia, malnutrition and the diminishment of patient quality of life (QOL). Self-expanding oesophageal stents are the most common approach to attenuate these symptoms. Recent advances in oncological therapy have enabled patient survival beyond the lifetime of current devices. This introduces new complications for palliation, driving the need for innovation in stent design. This review identifies the factors responsible for stent failure. It explores the challenges of enhancing the longevity of stent therapies and outlines solutions to improving clinical outcomes. Discussions focus on the role of stent materials, construction methods, and coatings upon device performance. We found three key stent enhancement strategies currently used; material surface treatments, anti-migratory modifications, and biodegradable skeletons. Furthermore, radioactive and drug eluting stent designs were identified as emerging novel treatments. In conclusion, the review offers an overview of remaining key challenges in oesophageal stent design and potential solutions. It is clear that further research is needed to improve the clinical outcome of stents and patient QOL.

Serotonin 5-HT7 Receptor Is A Biomarker Poor Prognostic Factor And Induces Proliferation of Triple Negative Breast Cancer Cells Through FOXM1

Purpose: Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer and associated with poor prognosis and shorter survival due to significant genetic heterogeneity, drug resistance and lack of effective targeted therapeutics. Therefore, novel molecular targets and therapeutic strategies are needed to improve patient survival. Serotonin (5-hydroxytriptamine, 5-HT) has been shown to induce growth stimulatory effects in breast cancer. However, the molecular mechanisms by which 5-HT exerts its oncogenic effects in TNBC still are not well understood. Methods: Normal breast epithelium (MCF10A) and two TNBC cells (MDA-MB-231, BT-546) and MCF-7 cells (ER+) were used to investigate effects of 5-HT7 receptor. Small interfering RNA (siRNA)-based knockdown and metergoline (5-HT7 antagonist) were used to inhibit the activity of 5-HT7. Cell proliferation and colony formation were evaluated using MTS cell viability and colony formation assays, respectively. Western blotting was used to investigate 5-HT7, FOXM1 and its downstream targets protein expressions.Results: We demonstrated that 5-HT induces cell proliferation of TNBC cells and expression of 5-HT7 receptor and FOXM1 oncogenic transcription factor. We found that expression of 5-HT7 receptor is upregulated in TNBC cells and higher 5-HT7 expression is associated with poor patient prognosis and shorter patient survival. Genetic and pharmacological inhibition of 5-HT7 by siRNA and metergoline, respectively, suppressed TNBC cell proliferation and FOXM1 and its downstream mediators, including eEF2-Kinase (eEF2K) and cyclin-D1. Conclusion: Our findings suggest for the first time that the 5-HT7 receptor promotes FOXM1, eEF2K and cyclin D1 signaling to support TNBC cell proliferation, thus inhibition of 5-HT7/FOXM1 signaling may be used as a potential therapeutic strategy for targeting TNBC.