Anti-Cancer Activity of Sustained Release Capsaicin Formulations

Capsaicin (trans-8-methyl-N-vanillyl-6-noneamide) is a hydrophobic, lipophilic vanilloid phytochemical abundantly found in chili peppers and pepper extracts. Several convergent studies show that capsaicin displays robust cancer activity, suppressing the growth, angiogenesis and metastasis of several human cancers. Despite its potent cancer-suppressing activity, the clinical applications of capsaicin as a viable anti-cancer drug have remained problematic due to its poor bioavailability and aqueous solubility properties. In addition, the administration of capsaicin is associated with adverse side effects like gastrointestinal cramps, stomach pain, nausea and diarrhea and vomiting. All these hurdles may be circumvented by encapsulation of capsaicin in sustained release drug delivery systems. Most of the capsaicin-based the sustained release drugs have been tested for their pain-relieving activity. Only a few of these formulations have been investigated as anti-cancer agents. The present review describes the physicochemical properties, bioavailability, and anti-cancer activity of capsaicin-sustained release agents. The asset of such continuous release capsaicin formulations is that they display better solubility, stability, bioavailability, and growth-suppressive activity than the free drug. The encapsulation of capsaicin in sustained release carriers minimizes the adverse side effects of capsaicin. In summary, these capsaicin-based sustained release drug delivery systems have the potential to function as novel chemotherapies, unique diagnostic imaging probes and innovative chemosensitization agents in human cancers

Causal Mediation Analysis for Difference-in-Difference Design and Panel Data

Advantages of panel data, i.e., difference in difference (DID) design data, are a large sample size and easy availability. Therefore, panel data are widely used in epidemiology and in all social science fields. The literatures on causal inferences of panel data setting or DID design are growing, but no theory or mediation analysis method has been proposed for such settings. In this study, we propose a methodology for conducting causal mediation analysis in DID design and panel data setting. We provide formal counterfactual definitions for controlled direct effect and natural direct and indirect effect in panel data setting and DID design, including the identification and required assumptions. We also demonstrate that, under the assumptions of linearity and additivity, controlled direct effects can be estimated by contrasting marginal and conditional DID estimators whereas natural indirect effects can be estimated by calculating the product of the exposure-mediator DID estimator and the mediator-outcome DID estimator. A panel regression-based approach is also proposed. The proposed method is then used to investigate mechanisms of the effects of the Covid 19 pandemic on the mental health status of the population. The results revealed that mobility restrictions mediated approximately 45 % of the causal effect of Covid 19 on mental health status

Partnering with Archivists to Process the Manuscript Collection Present at the Marshall University Herbarium

The Marshall University Herbarium (MUHW) is located on the third floor of the Science Building at Marshall University in Huntington, West Virginia, United States. It was founded in the 1930\u27s by Dr. Frank A. Gilbert when Marshall was still Marshall College. Today, MUHW is the second largest herbarium in West Virginia with about 50,000 specimens, including 20 types. Mostly composed of vascular plants, the herbarium also contains small collections of non-vascular plants, fungi, algae, fossils, and some ethnobotanical material, mainly brought from Ecuador by one of the former curators, Dr. Dan Evans between the 1980\u27s and 2000\u27s. Apart from these biological collections, the Herbarium also has a small library and many other documents from former curators: letters from 1920-1930 written by Dr. Gilbert during the early years of MUHW, and research, teaching, and personal documents from Dr. Evans. In order to process the documentation present in the Herbarium, the MUHW curator reached out to the chair of the Special Collections Department at Marshall University, whose focus is precisely on manuscript collections like this and their historical relevance to the University and the Huntington area

Lynn Margulis and Boris Kozo-Polyansky: How the Symbiogenesis was translated from Russian

This contribution details the complex history of the early work by Boris Kozo-Polyansky (1924) that became available in English translation 86 years after it was published in Russian. The great American naturalist Lynn Margulis—whose serial endosymbiosis theory was presciently predated by Kozo-Polyansky by four decades—was instrumental in organizing this resurrection and ‘horizontal transfer’ of knowledge, forgotten by that time even in Russia

Causal Mediation Analysis with Multiple Time-Varying Mediators

In longitudinal studies with time-varying exposures and mediators, the mediational g-formula is an important method for the assessment of direct and indirect effects. However, current methodologies based on the mediational g-formula can deal with only one mediator. This limitation makes these methodologies inapplicable to many scenarios. Hence, we develop a novel methodology by extending the mediational g-formula to cover cases with multiple time-varying mediators. We formulate two variants of our approach that are each suited to a distinct set of assumptions and effect definitions and present nonparametric identification results of each variant. We further show how complex causal mechanisms (whose complexity derives from the presence of multiple time-varying mediators) can be untangled. A parametric method along with a user-friendly algorithm was implemented in R software. We illustrate our method by investigating the complex causal mechanism underlying the progression of chronic obstructive pulmonary disease. We found that the effects of lung function impairment mediated by dyspnea symptoms and mediated by physical activity accounted for 13.7% and 10.8% of the total effect, respectively. Our analyses thus illustrate the power of this approach, providing evidence for the mediating role of dyspnea and physical activity on the causal pathway from lung function impairment to health status

Identification And Robust Estimation Of Swapped Direct And Indirect Effects: Mediation Analysis With Unmeasured Mediator–Outcome Confounding And Intermediate Confounding

Counterfactual-model-based mediation analysis can yield substantial insight into the causal mechanism through the assessment of natural direct effects (NDEs) and natural indirect effects (NIEs). However, the assumptions regarding unmeasured mediator–outcome confounding and intermediate mediator–outcome confounding that are required for the determination of NDEs and NIEs present practical challenges. To address this problem, we introduce an instrumental blocker, a novel quasi-instrumental variable, to relax both of these assumptions, and we define a swapped direct effect (SDE) and a swapped indirect effect (SIE) to assess the mediation. We show that the SDE and SIE are identical to the NDE and NIE, respectively, based on a causal interpretation. Moreover, the empirical expressions of the SDE and SIE are derived with and without an intermediate mediator–outcome confounder. Then, a bias formula is developed to examine the plausibility of the proposed instrumental blocker. Moreover, a multiply robust estimation method is derived to mitigate the model misspecification problem. We prove that the proposed estimator is consistent, asymptotically normal, and achieves the semiparametric efficiency bound. As an illustration, we apply the proposed method to genomic datasets of lung cancer to investigate the potential role of the epidermal growth factor receptor in the treatment of lung cancer

On The Conventional Definition Of Path-Specific Effects - fully mediated interaction with multiple ordered mediators

Path-specific effects (PSEs) are a critical measure for assessing mediation in the presence of multiple mediators. However, the conventional definition of PSEs has generated controversy because it often causes misinterpretation of the results of multiple mediator analysis. For in-depth analysis of this issue, we propose the concept of decomposing fully mediated interaction (FMI) from the average causal effect. We show that FMI misclassification is the main cause of PSE misinterpretation. Two strategies for specifying FMI are proposed: isolating FMI and reclassifying FMI. The choice of strategy depends on the objective. Isolating FMI is the superior strategy when the main objective is elucidating the mediation mechanism whereas reclassifying FMI is superior when the main objective is precisely interpreting the mediation analysis results. To compare performance, this study used the two proposed strategies and the conventional decomposition strategy to analyze the mediating roles of dyspnea and anxiety in the effect of impaired lung function on poor health status in a population of patients with chronic obstructive pulmonary disease. The estimation result showed that the conventional decomposition strategy underestimates the importance of dyspnea as a mechanism of this disease. Specifically, the strategy of reclassifying FMI revealed that 50% of the average causal effect is attributable to mediating effects, particularly the mediating effect of dyspnea

Ratio and Difference of Average Hazard with Survival Weight: New Measures to Quantify Survival Benefit of New Therapy

The hazard ratio (HR) has been the most popular measure to quantify the magnitude of treatment effect on time-to-event outcomes in clinical research. However, the HR estimated by Cox\u27s method has several drawbacks. One major issue is that there is no clear interpretation when the proportional hazards (PH) assumption does not hold, because it is affected by study-specific censoring time distribution in non-PH cases. Another major issue is that the lack of a group-specific absolute hazard value in each group obscures the clinical significance of the magnitude of the treatment effect. Given these, we propose average hazard with survival weight (AH-SW) as a summary metric of event time distribution and will use difference in AH-SW (DAH-SW) or ratio of AH-SW (RAH-SW) to quantify the treatment effect magnitude. The AH-SW we propose is a new digestible metric interpreted as a person-years event rate when random censoring would not exist. It is defined as the ratio of tau-year event rate and restricted mean survival time, which can be estimated non-parametrically. Numerical studies demonstrate that DAH-SW and RAH-SW offer almost identical power to Cox\u27s method under PH scenarios and can be more powerful for delayed-difference patterns that are often seen in immunotherapy trials. The proposed metrics (i.e., AH-SW, DAH-SW and RAH-SW) and the inferential methods for them offer a digestible interpretation that the conventional Cox\u27s method could not provide about the survival benefit of a new therapy. These metrics will increase the likelihood that results from clinical studies are correctly interpreted

Where Epigenetics Meets Food Intake: Their Interaction in the Development/Severity of Gout and Therapeutic Perspectives

Gout is the most frequent form of inflammatory arthritis in the world. Its prevalence is particularly elevated in specific geographical areas such as in the Oceania/Pacific region and is rising in the US, Europe, and Asia. Gout is a severe and painful disease, in which co-morbidities are responsible for a significant reduction in life expectancy. However, gout patients remain ostracized because the disease is still considered “self-inflicted”, as a result of unhealthy lifestyle and excessive food and alcohol intake. While the etiology of gout flares is clearly associated with the presence of monosodium urate (MSU) crystal deposits, several major questions remain unanswered, such as the relationships between diet, hyperuricemia and gout flares or the mechanisms by which urate induces inflammation. Recent advances have identified gene variants associated with gout incidence. Nevertheless, genetic origins of gout combined to diet-related possible uric acid overproduction account for the symptoms in only a minor portion of patients. Hence, additional factors must be at play. Here, we review the impact of epigenetic mechanisms in which nutrients (such as ω-3 polyunsaturated fatty acids) and/or dietary-derived metabolites (like urate) trigger anti/pro-inflammatory responses that may participate in gout pathogenesis and severity. We propose that simple dietary regimens may be beneficial to complement therapeutic management or contribute to the prevention of flares in gout patients

Epigenetic Reprogramming Mediated by Maternal Diet Rich in Omega-3 Fatty Acids Protects From Breast Cancer Development in F1 Offspring

Diets rich in omega-3 fatty acids (FA) have been associated with lowered risks of developing certain types of cancers. We earlier reported that in transgenic mice prone to develop breast cancer (BCa), a diet supplemented with canola oil, rich in omega-3-rich FA (as opposed to an omega-6-rich diet containing corn oil), reduced the risk of developing BCa, and also significantly reduced the incidence of BCa in F1 offspring. To investigate the underlying mechanisms of the cancer protective effect of canola oil in the F1 generation, we designed and performed the present study with the same diets using BALB/c mice to remove any possible effect of the transgene. First, we observed epigenetic changes at the genome-wide scale in F1 offspring of mothers fed diets containing omega-3 FAs, including a significant increase in acetylation of H3K18 histone mark and a decrease in H3K4me2 mark on nucleosomes around transcription start sites. These epigenetic modifications contribute to differential gene expressions associated with various pathways and molecular mechanisms involved in preventing cancer development, including p53 pathway, G2M checkpoint, DNA repair, inflammatory response, and apoptosis. When offspring mice were exposed to 7,12-Dimethylbenz(a)anthracene (DMBA), the group of mice exposed to a canola oil (with omega 3 FAs)-rich maternal diet showed delayed mortality, increased survival, reduced lateral tumor growth, and smaller tumor size. Remarkably, various genes, including BRCA genes, appear to be epigenetically re-programmed to poise genes to be ready for a rapid transcriptional activation due to the canola oil-rich maternal diet. This ability to respond rapidly due to epigenetic potentiation appeared to contribute to and promote protection against breast cancer after carcinogen exposure