Epigenetic Modulators as Treatment Alternative to Diverse Types of Cancer

DNA is packaged in rolls in an octamer of histones forming a complex of DNA and proteins called chromatin. Chromatin as a structural matrix of a chromosome and its modifications are nowadays considered relevant aspects for regulating gene expression, which has become of high interest in understanding genetic mechanisms regulating various diseases, including cancer. In various types of cancer, the main modifications are found to be DNA methylation in the CpG dinucleotide as a silencing mechanism in transcription, post-translational histone modifications such as acetylation, methylation and others that affect the chromatin structure, the ATP-dependent chromatin remodeling and miRNA-mediated gene silencing. In this review we analyze the main alterations in gene expression, the epigenetic modification patterns that cancer cells present, as well as the main modulators and inhibitors of each epigenetic mechanism and the molecular evolution of the most representative inhibitors, which have opened a promising future in the study of HAT, HDAC, non-glycoside DNMT inhibitors and domain inhibitors.

Hypoxia: The Cornerstone of Glioblastoma

Glioblastoma is the most aggressive form of brain tumor in adults and is characterized by the presence of hypervascularization and necrosis, both caused by a hypoxic microenvironment. In this review, we highlight that hypoxia-induced factor 1 (HIF-1), the main factor activated by hypoxia, is an important driver of tumor progression in GB patients. HIF-1α is a transcription factor regulated by the presence or absence of O2. The expression of HIF-1 has been related to high-grade gliomas and aggressive tumor behavior. HIF-1 promotes tumor progression via the activation of angiogenesis, immunosuppression, and metabolic reprogramming, promoting cell invasion and survival. Moreover, in GB, HIF-1 is not solely modulated by oxygen but also by oncogenic signaling pathways, such as MAPK/ERK, p53, and PI3K/PTEN. Therefore, the inhibition of the hypoxia pathway could represent an important treatment alternative in a disease with very few therapy options. Here, we review the roles of HIF-1 in GB progression and the inhibitors that have been studied thus far, with the aim of shedding light on this devastating disease.

High-Dose Rate Interstitial Spine Brachytherapy Using an Intraoperative Mobile Computed Tomography-Guided Surgical Navigation System

BACKGROUND Up to 15% of previously irradiated metastatic spine tumors will progress. Re-irradiation of these tumors poses a significant risk of exceeding the radiation tolerance to the spinal cord. High-dose rate (HDR) brachytherapy is a treatment alternative. OBJECTIVE To develop a novel HDR spine brachytherapy technique using an intraoperative computed tomography-guided navigation (iCT navigation). METHODS Patients with progressive metastatic spine tumors were included in the study. HDR brachytherapy catheters were placed under iCT navigation. CT-based planning with magnetic resonance imaging fusion was performed to ensure conformal dose delivery to the target while sparing normal tissue, including the spinal cord. Patients received single fraction radiation treatment. RESULTS Five patients with thoracolumbar tumors were treated with HDR brachytherapy. Four patients previously received radiotherapy to the same spinal level. Preimplant plans demonstrated median clinical target volume (CTV) D90 of 116.5% (110.8%-147.7%), V100 of 95.7% (95.5%-99.6%), and Dmax of 8.08 Gy (7.65-9.8 Gy) to the spinal cord/cauda equina. Postimplant plans provided median CTV D90 of 113.8% (93.6%-120.1%), V100 of 95.9% (87%-99%), and Dmax of 9.48 Gy (6.5-10.3 Gy) to cord/cauda equina. Patients who presented with back pain (n = 3) noted symptomatic improvement at a median follow-up of 22 d after treatment. Four patients demonstrated local tumor control of spinal metastatic tumor at a median follow-up of 92 d after treatment. One patient demonstrated radiographic evidence of local tumor progression 2.7 mo after treatment. CONCLUSION HDR spine brachytherapy with iCT navigation is a promising treatment alternative to induce local tumor control and reduce pain symptoms associated with metastatic spine disease.

Efficacy of platelet-rich plasma and plasma for symptomatic treatment of knee osteoarthritis: a double-blinded placebo-controlled randomized clinical trial

Background Platelet-rich plasma (PRP) has a still conflicting efficacy for knee osteoarthritis (KOA) and might be a minimally invasive and safe treatment alternative. The potential benefit of only plasma (non-enriched) has never been investigated. Our aim was to evaluate the efficacy of intra-articular platelet-rich plasma (PRP) and plasma to improve pain and function in participants with KOA over 24 weeks. Methods Randomized, double-blind, placebo-controlled trial with 3 groups (n = 62): PRP (n = 20), plasma (n = 21) and saline (n = 21). Two ultrasound-guided knee injections were performed with a 2-week interval. The primary outcome was visual analog scale 0-10 cm (VAS) for overall pain at week 24, with intermediate assessments at weeks 6 and 12. Main secondary outcomes were: KOOS, OMERACT-OARSI criteria and TUGT. Results At baseline, 92% of participants were female, with a mean age of 65 years, mean BMI of 28.0 Kg/m2and mean VAS pain of 6.2 cm. Change in pain from baseline at week 24 were -2.9 (SD 2.5), -2.4 (SD 2.5) and -3.5 cm (SD 3.3) for PRP, plasma and saline, respectively (p intergroup = 0.499). There were no differences between the three groups at weeks 6 and 12. Similarly, there were no differences between groups regarding secondary outcomes. The PRP group showed higher frequency of adverse events (65% versus 24% and 33% for plasma and saline, respectively, p = 0.02), mostly mild transitory increase in pain. Conclusions PRP and plasma were not superior to placebo for pain and function improvement in KOA over 24 weeks. The PRP group had a higher frequency of mild transitory increase in pain. Trial registration ClinicalTrials.gov, NCT03138317, 03/05/2017.

Therapeutic roles of mesenchymal stem cell-derived extracellular vesicles in cancer

Extracellular vesicles (EVs) are cell-derived membrane structures enclosing proteins, lipids, RNAs, metabolites, growth factors, and cytokines. EVs have emerged as essential intercellular communication regulators in multiple physiological and pathological processes. Previous studies revealed that mesenchymal stem cells (MSCs) could either support or suppress tumor progression in different cancers by paracrine signaling via MSC-derived EVs. Evidence suggested that MSC-derived EVs could mimic their parental cells, possessing pro-tumor and anti-tumor effects, and inherent tumor tropism. Therefore, MSC-derived EVs can be a cell-free cancer treatment alternative. This review discusses different insights regarding MSC-derived EVs' roles in cancer treatment and summarizes bioengineered MSC-derived EVs’ applications as safe and versatile anti-tumor agent delivery platforms. Meanwhile, current hurdles of moving MSC-derived EVs from bench to bedside are also discussed.

The mechanobiology of craniosynostosis in Crouzon syndrome

Children with syndromic forms of craniosynostosis undergo a plethora of surgical interventions to resolve the clinical features caused by the premature fusion of cranial sutures. While surgical correction is reliable, the need for repeated rounds of invasive treatment puts a heavy burden on the child and their family. This study explores a non-surgical alternative using mechanical loading of the cranial bones to prevent or delay craniosynostosis and its effects. We treated Crouzon syndrome mice before the onset of craniosynostosis by mechanical loading of cranial bones. Cranial loading applied to the frontal bone caused partial normalisation of skull shape, reducing the typical brachycephalic appearance. This is underpinned by the delayed closure of the coronal suture and of the intersphenoidal synchondrosis. This study provides a novel treatment alternative for syndromic craniosynostosis which has the potential to be an important step towards replacing, reducing or refining the surgical treatment of craniosynostosis patients.

Research of Alternative Options for Strengthening Surface Treatment of Cast Iron Products

The article considers issues of increasing wear resistance of cast iron products by methods of thermochemical treatment of their surface layer. Methods are proposed to solve the problem of wear from cast iron of grade EN-JS1060 due to development of technological processes of strengthening treatment. Alternative versions of strengthening technologies are represented by nitrocarburizing, liquid nitriding and carbonitration. Results of examination of control samples at increasing loads after 200 N before catastrophic wear are given. Comparative analysis of these results showed that samples after carbonitration and liquid nitriding had the greatest bearing capacity (1000 N). Carbonitration is selected as a most preferred option of the surface hardening treatment. Non-poisonous cyanoacid salts are used to realize it.

Factors associated with the effectiveness of part-time patching for intermittent exotropia in children

Purpose: To evaluate the factors associated with the efficacy of low-dose part-time patching in children with intermittent exotropia (IXT). Methods: In this prospective observational study, we enrolled 186 patients diagnosed with IXT. Outcome measures included office based control scales, magnitude of exo-deviation, and stereoacuity at near and distance after daily patching for 2 h. We analyzed the clinical data and demographic factors association with improvement of IXT. Results: The study was completed by 152 subjects of total enrolled patients on a consecutive basis followed up for 1 year. Decrease in the magnitude of exo-deviation, improvement of control, and or gain of stereoacuity were observed in 31.6% patients of the recruited subjects after part-time patching. Multivariate analyses showed that prognostic factors determining improvement to part-time patching included convergence insufficiency (CI) type IXT ( p = 0.016), poor distance stereopsis ( p = 0.044), and large exotropic deviation at distance ( p = 0.025). Conclusions: CI-type exotropia, large distance magnitude of exo-deviation, or poor distance stereopsis appear to be associated with a better response to part-time patching. Therefore low dose part-time patching may be a useful non-surgical treatment alternative to delay surgery in these cases.

Comparison of Skin Substitutes for Acute and Chronic Wound Management

Chronic and acute wounds, such as diabetic foot ulcers and burns, respectively, can be difficult to treat, especially when autologous skin transplantations are unavailable. Skin substitutes can be used as a treatment alternative by providing the structural elements and growth factors necessary for reepithelialization and revascularization from a nonautologous source. As of 2020, there are 76 commercially available skin substitute products; this article provides a review of the relevant literature related to the major categories of skin substitutes available.