Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer

Aberrant DNA methylation observed in cancer can provide survival benefits to cells by silencing genes essential for anti-tumor activity. DNA-demethylating agents such as Decitabine (DAC)/Azacitidine (AZA) activate otherwise silenced tumor suppressor genes, alter immune response and epigenetically reprogram tumor cells. In this study, we show that non-cytotoxic nanomolar DAC concentrations modify the bladder cancer transcriptome to activate NOTCH1 at the mRNA and protein level, increase double-stranded RNA sensors and CK5-dependent differentiation. Importantly, DAC treatment increases ICN1 expression (the active intracellular domain of NOTCH1) significantly inhibiting cell proliferation and causing changes in cell size inducing morphological alterations reminiscent of senescence. These changes were not associated with β-galactosidase activity or increased p16 levels, but instead were associated with substantial IL-6 release. Increased IL-6 release was observed in both DAC-treated and ICN1 overexpressing cells as compared to control cells. Exogenous IL-6 expression was associated with a similar enlarged cell morphology that was rescued by the addition of a monoclonal antibody against IL-6. Treatment with DAC, overexpression with ICN1 or addition of exogenous IL-6 showed CK5 reduction, a surrogate marker of differentiation. Overall this study suggests that in MIBC cells, DNA hypomethylation increases NOTCH1 expression and IL-6 release to induce CK5-related differentiation.Fil: Ramakrishnan, Swathi. Roswell Park Cancer Institute; Estados UnidosFil: Hu, Qiang. Roswell Park Cancer Institute; Estados UnidosFil: Krishnan, Nithya. Roswell Park Cancer Institute; Estados UnidosFil: Wang, Dan. Roswell Park Cancer Institute; Estados UnidosFil: Smit, Evelyn. Roswell Park Cancer Institute; Estados UnidosFil: Granger, Victoria. Roswell Park Cancer Institute; Estados UnidosFil: Rak, Monika. Jagiellonian University; PoloniaFil: Attwood, Kristopher. Roswell Park Cancer Institute; Estados UnidosFil: Johnson, Candace. Roswell Park Cancer Institute; Estados UnidosFil: Morrison, Carl. Roswell Park Cancer Institute; Estados UnidosFil: Pili, Roberto. Indiana University; Estados UnidosFil: Chatta, Gurkamal. Roswell Park Cancer Institute; Estados UnidosFil: Guru, Khurshid. Roswell Park Cancer Institute; Estados UnidosFil: Gueron, Geraldine. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: McNally, Lacey. University of Louisville; Estados UnidosFil: Wang, Jianmin. Roswell Park Cancer Institute; Estados UnidosFil: Woloszynska-Read, Anna. Roswell Park Cancer Institute; Estados Unido

The RAZOR (randomized open vs robotic cystectomy) trial: study design and trial update

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110540/1/bju12699.pd

Prior-Independent Auctions for Heterogeneous Bidders

We study the design of prior-independent auctions in a setting with heterogeneous bidders. In particular, we consider the setting of selling to $n$ bidders whose values are drawn from $n$ independent but not necessarily identical distributions. We work in the robust auction design regime, where we assume the seller has no knowledge of the bidders' value distributions and must design a mechanism that is prior-independent. While there have been many strong results on prior-independent auction design in the i.i.d. setting, not much is known for the heterogeneous setting, even though the latter is of significant practical importance. Unfortunately, no prior-independent mechanism can hope to always guarantee any approximation to Myerson's revenue in the heterogeneous setting; similarly, no prior-independent mechanism can consistently do better than the second-price auction. In light of this, we design a family of (parametrized) randomized auctions which approximates at least one of these benchmarks: For heterogeneous bidders with regular value distributions, our mechanisms either achieve a good approximation of the expected revenue of an optimal mechanism (which knows the bidders' distributions) or exceeds that of the second-price auction by a certain multiplicative factor. The factor in the latter case naturally trades off with the approximation ratio of the former case. We show that our mechanism is optimal for such a trade-off between the two cases by establishing a matching lower bound. Our result extends to selling $k$ identical items to heterogeneous bidders with an additional $O\big(\ln^2 k\big)$-factor in our trade-off between the two cases

The Power of Menus in Contract Design

We study the power of menus of contracts in principal-agent problems with adverse selection (agents can be one of several types) and moral hazard (we cannot observe agent actions directly). For principal-agent problems with $T$ types and $n$ actions, we show that the best menu of contracts can obtain a factor $\Omega(\max(n, \log T))$ more utility for the principal than the best individual contract, partially resolving an open question of Guruganesh et al. (2021). We then turn our attention to randomized menus of linear contracts, where we likewise show that randomized linear menus can be $\Omega(T)$ better than the best single linear contract. As a corollary, we show this implies an analogous gap between deterministic menus of (general) contracts and randomized menus of contracts (as introduced by Castiglioni et al. (2022)).Comment: EC 202

Development and Stability Studies of Novel Liposomal Vancomycin Formulations

A promising strategy to improve the therapeutic efficiency of antimicrobial agents is targeted therapy. Although vancomycin has been considered a gold standard for the therapy of MRSA pneumonia, clinical failure rates have also been reported owing to its slow, time-dependent bactericidal activity, variable lung tissue penetration and poor intracellular penetration into macrophages. Liposomal encapsulation has been established as an alternative for antimicrobial delivery to infected tissue macrophages and offers enhanced pharmacodynamics, pharmacokinetics and decreased toxicity compared to standard preparations. The aim of the present work is to prepare vancomycin in two different liposomal formulations, conventional and PEGylated liposomes using different methods. The prepared formulations were optimized for their particle size, encapsulation efficiency and physical stability. The dehydration-rehydration was found to be the best preparation method. Both the conventional and PEGylated liposomal formulations were successfully formulated with a narrow particle size and size distribution and % encapsulation efficiency of 9 ± 2 and 12 ± 3, respectively. Both the formulations were stable at 4°C for 3 months. These formulations were successfully used to evaluate for their intracellular killing of MRSA and in vivo pharmacokinetic and bio-distribution studies

Vanadium Oxide Thin-Film Variable Resistor-Based RF Switches

Vanadium dioxide (VO2) is a unique phase change material (PCM) that possesses a metal-to-insulator transition property. Pristine VO2 has a negative temperature coefficient of resistance, and it undergoes an insulator-to-metal phase change at a transition temperature of 68°C. Such a property makes the VO2 thin-film-based variable resistor (varistor) a good candidate in reconfigurable electronics to be integrated with different RF devices such as inductors, varactors, and antennas. Series single-pole single-throw (SPST) switches with integrated VO2 thin films were designed, fabricated, and tested. The overall size of the device is 380 μm × 600 μm. The SPST switches were fabricated on a sapphire substrate with integrated heating coil to control VO2 phase change. During the test, when VO2 thin film changed from insulator at room temperature to metallic state (low-resistive phase) at 80 °C, the insertion loss of the SPST switch wasaddition, the isolation of the SPST improved to better than 30 dB when the temperature dropped to 20 °C. These tunable characteristics of the RF switch provide evidence for VO2 as a useful PCM for of applications in reconfigurable electronics

Binder free, Thin-Film Ceramic Coated Separators for Improved Safety of Lithium-Ion Batteries

With the rapid development of lithium-ion batteries (LIBs), safety issues are the greatest obstacles that restrict their large scale-applications, especially for the high-energy-density electric vehicle and aviation industry. Separators play a crucial role in ensuring the safety of LIBs. However, due to their poor thermal stability, commercial polyolefin-based separators such as polyethylene (PE) still possess serious safety risks under abuse conditions. To address these challenges, a novel type of binder-free, thin ceramic-coated separator with superior safety characteristics is demonstrated in this research.https://ecommons.udayton.edu/grad_showcase/1006/thumbnail.jp

Digital watermarking : applicability for developing trust in medical imaging workflows state of the art review

Medical images can be intentionally or unintentionally manipulated both within the secure medical system environment and outside, as images are viewed, extracted and transmitted. Many organisations have invested heavily in Picture Archiving and Communication Systems (PACS), which are intended to facilitate data security. However, it is common for images, and records, to be extracted from these for a wide range of accepted practices, such as external second opinion, transmission to another care provider, patient data request, etc. Therefore, confirming trust within medical imaging workflows has become essential. Digital watermarking has been recognised as a promising approach for ensuring the authenticity and integrity of medical images. Authenticity refers to the ability to identify the information origin and prove that the data relates to the right patient. Integrity means the capacity to ensure that the information has not been altered without authorisation. This paper presents a survey of medical images watermarking and offers an evident scene for concerned researchers by analysing the robustness and limitations of various existing approaches. This includes studying the security levels of medical images within PACS system, clarifying the requirements of medical images watermarking and defining the purposes of watermarking approaches when applied to medical images

Selenium Yeast Dietary Supplement Affects Rumen Bacterial Population Dynamics and Fermentation Parameters of Tibetan Sheep (

Selenium (Se) deficiency is a widespread and seasonally chronic phenomenon observed in Tibetan sheep (Ovis aries) traditionally grazed on the Qinghai–Tibet Plateau (QTP). Effects of the dietary addition of Se-enriched yeast (SeY) on the bacterial community in sheep rumen and rumen fermentation were evaluated with the aim of gaining a better understanding of the rumen prokaryotic community. Twenty-four yearling Tibetan rams [initial average body weight (BW) of 31.0 ± 0.64 kg] were randomly divided into four treatment groups, namely, control (CK), low Se (L), medium Se (M), and high Se (H). Each group comprised six rams and was fed a basic diet of fresh forage cut from the alpine meadow, to which SeY was added at prescribed dose rates. This feed trial was conducted for over 35 days. On the final day, rumen fluid was collected using a transesophageal sampler for analyzing rumen pH, NH3-N content, volatile fatty acid (VFA) level, and the rumen microbial community. Our analyses showed that NH3-N, total VFA, and propionate concentrations in the M group were significantly higher than in the other groups (P < 0.05). Both the principal coordinates analysis (PCoA) and the analysis of similarities revealed that the bacterial population structure of rumen differed among the four groups. The predominant rumen bacterial phyla were found to be Bacteroidetes and Firmicutes, and the three dominant genera in all the samples across all treatments were Christensenellaceae R7 group, Rikenellaceae RC9 gut group, and Prevotella 1. The relative abundances of Prevotella 1, Rikenellaceae RC9 gut group, Ruminococcus 2, Lachnospiraceae XPB1014 group, Carnobacterium, and Hafnia-Obesumbacterium were found to differ significantly among the four treatment groups (P < 0.05). Moreover, Tax4fun metagenome estimation revealed that gene functions and metabolic pathways associated with carbohydrate and other amino acids were overexpressed in the rumen microbiota of SeY-supplemented sheep. To conclude, SeY significantly affects the abundance of rumen bacteria and ultimately affects the rumen microbial fermentation