Lipid nanoparticles delivering constitutively active STING mRNA as a novel anti-cancer therapeutic approach

Treating immunosuppressive tumors represents a major challenge in cancer therapies. Activation of STING signaling has shown remarkable potential to invigorate the immunologically 'cold' tumor microenvironment (TME). However, we and others have shown that STING is silenced in many cancers, including pancreatic ductal adenocarcinoma (PDAC) and Merkel cell carcinoma (MCC), both of which are associated with an immune-dampened TME. In this study, we applied mRNA lipid nanoparticles (LNP) to deliver a permanently active gain-of-function STINGR284S mutant into PDAC and MCC cells. Expression of STINGR284S induces cytokines and chemokines crucial for promoting intratumoral infiltration of CD8+ T cells and, importantly, also leads to robust cancer cell death while avoiding T cell entry and toxicity. Our studies demonstrated that mRNA-LNP delivery of STINGR284S could be explored as a novel therapeutic tool to reactivate antitumor response in an array of STING-deficient cancers while overcoming the toxicity and limitations of conventional STING agonists.

VLCKD: a real time safety study in obesity

Background Very Low-Calorie Ketogenic Diet (VLCKD) is currently a promising approach for the treatment of obesity. However, little is known about the side effects since most of the studies reporting them were carried out in normal weight subjects following Ketogenic Diet for other purposes than obesity. Thus, the aims of the study were: (1) to investigate the safety of VLCKD in subjects with obesity; (2) if VLCKD-related side effects could have an impact on its efficacy. Methods In this prospective study we consecutively enrolled 106 subjects with obesity (12 males and 94 females, BMI 34.98 ± 5.43 kg/m2) that underwent to VLCKD. In all subjects we recorded side effects at the end of ketogenic phase and assessed anthropometric parameters at the baseline and at the end of ketogenic phase. In a subgroup of 25 subjects, we also assessed biochemical parameters. Results No serious side effects occurred in our population and those that did occur were clinically mild and did not lead to discontinuation of the dietary protocol as they could be easily managed by healthcare professionals or often resolved spontaneously. Nine (8.5%) subjects stopped VLCKD before the end of the protocol for the following reasons: 2 (1.9%) due to palatability and 7 (6.1%) due to excessive costs. Finally, there were no differences in terms of weight loss percentage (13.5 ± 10.9% vs 18.2 ± 8.9%; p = 0.318) in subjects that developed side effects and subjects that did not developed side effects. Conclusion Our study demonstrated that VLCKD is a promising, safe and effective therapeutic tool for people with obesity. Despite common misgivings, side effects are mild, transient and can be prevented and managed by adhering to the appropriate indications and contraindications for VLCKD, following well-organized and standardized protocols and performing adequate clinical and laboratory monitoring.

Effects of carrier solutions on the viability and efficacy of canine adipose-derived mesenchymal stem cells

Background Mesenchymal stem cells (MSCs) have favorable characteristics that render them a potent therapeutic tool. We tested the characteristics of MSCs after temporal storage in various carrier solutions, such as 0.9% saline (saline), 5% dextrose solution (DS), heparin in saline, and Hartmann’s solution, all of which are approved by the U.S. Food and Drug Administration (FDA). Phosphate-buffered saline, which does not have FDA approval, was also used as a carrier solution. We aimed to examine the effects of these solutions on the viability and characteristics of MSCs to evaluate their suitability and efficacy for the storage of canine adipose-derived MSCs (cADMSCs). Results We stored the cADMSCs in the test carrier solutions in a time-dependent manner (1, 6, and 12 h) at 4 °C, and analyzed cell confluency, viability, proliferation, self-renewability, and chondrogenic differentiation. Cell confluency was significantly higher in 5% DS and lower in phosphate-buffered saline at 12 h compared to other solutions. cADMSCs stored in saline for 12 h showed the highest viability rate. However, at 12 h, the proliferation rate of cADMSCs was significantly higher after storage in 5% DS and significantly lower after storage in saline, compared to the other solutions. cADMSCs stored in heparin in saline showed superior chondrogenic capacities at 12 h compared to other carrier solutions. The expression levels of the stemness markers, Nanog and Sox2, as well as those of the MSC surface markers, CD90 and CD105, were also affected over time. Conclusion Our results suggest that MSCs should be stored in saline, 5% DS, heparin in saline, or Hartmann’s solution at 4 °C, all of which have FDA approval (preferable storage conditions: less than 6 h and no longer than 12 h), rather than storing them in phosphate-buffered saline to ensure high viability and efficacy.

Nanoparticle-Based Modification of the DNA Methylome: A Therapeutic Tool for Atherosclerosis?

Cardiovascular epigenomics is a relatively young field of research, yet it is providing novel insights into gene regulation in the atherosclerotic arterial wall. That information is already pointing to new avenues for atherosclerosis (AS) prevention and therapy. In parallel, advances in nanoparticle (NP) technology allow effective targeting of drugs and bioactive molecules to the vascular wall. The partnership of NP technology and epigenetics in AS is just beginning and promises to produce novel exciting candidate treatments. Here, we briefly discuss the most relevant recent advances in the two fields. We focus on AS and DNA methylation, as the DNA methylome of that condition is better understood in comparison with the rest of the cardiovascular disease field. In particular, we review the most recent advances in NP-based delivery systems and their use for DNA methylome modification in inflammation. We also address the promises of DNA methyltransferase inhibitors for prevention and therapy. Furthermore, we emphasize the unique challenges in designing therapies that target the cardiovascular epigenome. Lastly, we touch the issue of human exposure to industrial NPs and its impact on the epigenome as a reminder of the undesired effects that any NP-based therapy must avoid to be apt for secondary prevention of AS.

Pleuroskopi Sebagai Tindakan Diagnostik pada Paru

Pleuroscopy, also known as medical thoracoscopy, is a minimally invasive procedure that is used to examine and biopsy the pleural cavity as well as to perform therapeutic interventions. This procedure has a near-perfect diagnostic accuracy in malignant pleural effusions and tuberculosis. With a mortality rate of 0.1%, the complication rate is low (2% - 5%) and usually mild (subcutaneous emphysema, bleeding, infection). Objective : Increase knowledge of pleuroscopy as a diagnostic and therapeutic tool in lung disease. Method : This paper is based on a review of the literature on pleuroscopy. Conclusion : Pleuroscopy is a minimally invasive procedure that can be used to examine and biopsy the pleural cavity, as well as for therapeutic intervention. Complications are uncommon and usually minor. Sugestion : Other articles are required to increase knowledge about pleuroscopy in order to obtain more knowledge.

Mandala Coloring as a Therapeutic Tool in Treating Stress-Anxiety-Depression Syndrome

Mandalas (in Sanskrit refers to “circle” or “discoid object”) have been exclusively a part of the Eastern religions such as Hinduism, Buddhism, Taoism, Jainism and Shintoism, for hundreds of years. They represent the different aspects of the universe. They are also used as sacred meditation tools as well as consecrated symbols of prayer, most notably in China, Japan, and Tibet. Only in recent years that mandalas have been found to promote the mental as well as physical well-being or wellness, especially for those who are experiencing stress, anxiety and depression (also known as SAD syndrome). They are eventually incorporated into art as therapy and counseling as part of the repertoire of intervention tools. Generally, mandala art therapy can be divided into three different forms: (i) mandala meditation, (ii) mandala drawing, and (iii) mandala coloring. Each of these forms is a therapeutic tool that serves to help a person to relax and be at peace with oneself. According to Jungian concept of a mandala, it refers to the psychological expression of the totality of the self, and hence, mandala art therapy in whichever of its three forms can help to establish the positive wholesomeness of self. In this paper, the authors have chosen to focus on mandala coloring as a therapeutic tool and introduced the simple five-step procedure to implement it.