Metformin as a Therapeutic Target in Endometrial Cancers.

Endometrial cancer is the most common gynecologic malignancy in developed countries. Its increasing incidence is thought to be related in part to the rise of metabolic syndrome, which has been shown to be a risk factor for the development of hyperestrogenic and hyperinsulinemic states. This has consequently lead to an increase in other hormone-responsive cancers as well e.g., breast and ovarian cancer. The correlation between obesity, hyperglycemia, and endometrial cancer has highlighted the important role of metabolism in cancer establishment and persistence. Tumor-mediated reprogramming of the microenvironment and macroenvironment can range from induction of cytokines and growth factors to stimulation of surrounding stromal cells to produce energy-rich catabolites, fueling the growth, and survival of cancer cells. Such mechanisms raise the prospect of the metabolic microenvironment itself as a viable target for treatment of malignancies. Metformin is a biguanide drug that is a first-line treatment for type 2 diabetes that has beneficial effects on various markers of the metabolic syndrome. Many studies suggest that metformin shows potential as an adjuvant treatment for uterine and other cancers. Here, we review the evidence for metformin as a treatment for cancers of the endometrium. We discuss the available clinical data and the molecular mechanisms by which it may exert its effects, with a focus on how it may alter the tumor microenvironment. The pleiotropic effects of metformin on cellular energy production and usage as well as intercellular and hormone-based interactions make it a promising candidate for reprogramming of the cancer ecosystem. This, along with other treatments aimed at targeting tumor metabolic pathways, may lead to novel treatment strategies for endometrial cancer

Practice analysis of certified public accountants: technical report

https://egrove.olemiss.edu/aicpa_assoc/1354/thumbnail.jp

Identifying Behavioral Health Needs of Individuals Screened at the Booking Counter of Montgomery County Jail

Background: Many of the individuals who are released from incarceration are re-arrested and re-incarcerated within three years of release. Challenges that predispose individuals to re-arrest and re-incarceration include lack of education, employment opportunities, decent affordable housing, and treatment for substance use disorders (SUD) and/or mental illness. This report summarizes the behavioral health needs of newly arrested individuals in Montgomery County, Ohio.Methods: For this project, 4,809 adult individuals arrested for non-violent crimes received behavioral health screening and case management at booking in the Montgomery County Jail. Criminogenic assessment using the Risk-Needs-Responsivity (RNR) tool was conducted with 484 arrestees. Descriptive statistics and chi square statistics were calculated for gender, race, referrals made, education level, employment status, housing status, alcohol and other drug use, and mental health status.Results: As a group, the arrestees were undereducated, underemployed, and homeless. Based on RNR assessment, 67% had an SUD,and 60% required mental health treatment. Significant gender and racial differences were found among the arrestees, with womensignificantly more likely to have SUD and mental health issues.Conclusions: Individuals arrested and booked into the Montgomery County Jail experience a complex interaction among mental health, poly-substance use, medical, employment, and housing needs that must be addressed in a comprehensive and coordinated funding manner. This interactive complexity of issues demand a response from an integrated service delivery system that would best benefit the person served and the community

Water Sublimation and Surface Temperature Simulations of Ceres

Ceres is one of the major objects of the main belt. Using a cometary-like model, we study the water sublimation and the surface temperature

Ceres: ice stability and water emission

Recent observations of H2O vapor plumes in localized regions [1] suggest the presence of ice on surface and/or on sub-surface regions of asteroid Ceres. In the hypothesis of a cometary-like emission mechanism (as already suggested by [2]), we performed several simulations in order to establish what are the likely physical conditions (in particular ice depth and thermal conductivity of crust) to fit Herschel observations [1]

Control and stabilization of waves on 1-d networks

We present some recent results on control and stabilization of waves on 1-d networks.The fine time-evolution of solutions of wave equations on networks and, consequently, their control theoretical properties, depend in a subtle manner on the topology of the network under consideration and also on the number theoretical properties of the lengths of the strings entering in it. Therefore, the overall picture is quite complex.In this paper we summarize some of the existing results on the problem of controllability that, by classical duality arguments in control theory, can be reduced to that of observability of the adjoint uncontrolled system. The problem of observability refers to that of recovering the total energy of solutions by means of measurements made on some internal or external nodes of the network. They lead, by duality, to controllability results guaranteeing that L 2-controls located on those nodes may drive sufficiently smooth solutions to equilibrium at a final time. Most of our results in this context, obtained in collaboration with R. Dáger, refer to the problem of controlling the network from one single external node. It is, to some extent, the most complex situation since, obviously, increasing the number of controllers enhances the controllability properties of the system. Our methods of proof combine sidewise energy estimates (that in the particular case under consideration can be derived by simply applying the classical d'Alembert's formula), Fourier series representations, non-harmonic Fourier analysis, and number theoretical tools.These control results belong to the class of the so-called open-loop control systems.We then discuss the problem of closed-loop control or stabilization by feedback. We present a recent result, obtained in collaboration with J. Valein, showing that the observability results previously derived, regardless of the method of proof employed, can also be recast a posteriori in the context of stabilization, so to derive explicit decay rates (as) for the energy of smooth solutions. The decay rate depends in a very sensitive manner on the topology of the network and the number theoretical properties of the lengths of the strings entering in it.In the end of the article we also present some challenging open problems

Short-term treatment with multi-drug regimens combining BRAF/MEK-targeted therapy and immunotherapy results in durable responses in Braf-mutated melanoma

Targeted and immunotherapy regimens have revolutionized the treatment of advanced melanoma patients. Despite this, only a subset of patients respond durably. Recently, combination strategies of BRAF/MEK inhibitors with immune checkpoint inhibitor monotherapy (α-CTLA-4 or α-PD-1) have increased the rate of durable responses. Based on evidence from our group and others, these therapies appear synergistic, but at the cost of significant toxicity. We know from other treatment paradigms (e.g. hematologic malignancies) that combination strategies with multi-drug regimens (\u3e4 drugs) are associated with more durable disease control. To better understand the mechanism of these improved outcomes, and to identify and prioritize new strategies for testing, we studied several multi-drug regimens combining BRAF/MEK targeted therapy and immunotherapy combinations in a Braf-mutant murine melanoma model (BrafV600E/Pten−/−). Short-term treatment with α-PD-1 and α-CTLA-4 monotherapies were relatively ineffective, while treatment with α-OX40 demonstrated some efficacy [17% of mice with no evidence of disease, (NED), at 60-days]. Outcomes were improved in the combined α-OX40/α-PD-1 group (42% NED). Short-term treatment with quadruplet therapy of immunotherapy doublets in combination with targeted therapy [dabrafenib and trametinib (DT)] was associated with excellent tumor control, with 100% of mice having NED after combined DT/α-CTLA-4/α-PD-1 or DT/α-OX40/α-PD-1. Notably, tumors from mice in these groups demonstrated a high proportion of effector memory T cells, and immunologic memory was maintained with tumor re-challenge. Together, these data provide important evidence regarding the potential utility of multi-drug therapy in treating advanced melanoma and suggest these models can be used to guide and prioritize combinatorial treatment strategies

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Thermal inertia of Occator's faculae on Ceres

Thermal inertia is a key information to quantify the physical status of a planetary surface; it can be retrieved by comparison between theoretical and observed temperature diurnal profiles. We have calculated the surface temperature for a set of locations on Ceres' surface with a thermophysical model that provides temperature as a function of thermal conductivity and roughness, and we have determined the values of those parameters for which the best fit with the observed data is obtained. The observed temperatures have been retrieved form spatially-resolved data from the Dawn mission. In our previous work [Rognini et al., 2019], we have found that the average thermal inertia for the overall surface of Ceres is low (from 1 to 15 to 60 J m^-2 s^1⁄2 K^-1), as expected according to the general trend observed in the Solar System for atmosphere-less bodies, while the thermal inertia of the very bright faculae found in the floor of the Occator crater could not be well defined. Using more recently acquired VIR high resolution data we find that the central part of the Cerealia facula displays a thermal anomaly (~ 10 K above the average) compatible with a higher thermal inertia with respect to the surrounding regions, while the Vinalia facula does not display any consequently could have a grain size comparable with the Ceres’ surface average