Can we predict reactivity for aromatic nucleophilic substitution with [ 18 F]fluoride ion?

The correlation between the 13 C‐NMR chemical shift of the aromatic ring carbon bearing the leaving group and the yield of nucleophilic aromatic displacement with no‐carrier‐added [ 18 F]fluoride ion was evaluated. In comparison of structurally analogous compounds (fluoro, nitro and trimethylammonium substituted benzaldehydes, benzophenones and benzonitriles), the 13 C‐NMR chemical shift of the reactive aryl ring carbon correlated quite well with the [ 18 F]fluorination yield (r 2 =0.87) for most but not all ring structures. Compounds with trimethylammonium leaving groups or methyl ring substituents were found to not fit the proposed correlation. Kinetic studies indicated clearly different rates of reaction for these compounds, with much higher than expected reactivity for the ccompounds with the cationic leaving group. Competition experiments suggest that low reactivity of methyl‐substituted rings may be due to conversion of [ 18 F]fluoride to an unreactive form. Our results indicate that the correlation between [ 18 F]fluorination yields for nucleophilic aromatic substitution reactions and the 13 C NMR chemical shift of the aryl ring carbon bearing the leaving group is applicable to numerous structurally analogous compounds, but cannot be simply generalized to aromatic rings with different leaving groups or ring substituents.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90183/1/2580330702_ftp.pd

Characterizing a source of fission fragments for a gas jet

A model for the rate at which various primary fission products stop in the gas of the source chamber of a gas jet has been constructed. It describes the absorption of fission fragments in Al foils placed between the 235 U deposit and the gas chamber as well as the penetration of fragments through the gas. The model is based on reported ranges (mean values as a function of A and the dispersion in ranges) and measured activities of Kr and Xe.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43112/1/10967_2005_Article_BF02060552.pd

Endoplasmic reticulum stress and cell death in mTORC1-overactive cells is induced by nelfinavir and enhanced by chloroquine

Inappropriate activation of mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is common in cancer and has many cellular consequences including elevated endoplasmic reticulum (ER) stress. Cells employ autophagy as a critical compensatory survival mechanism during ER stress. This study utilised drug-induced ER stress through nelfinavir in order to examine ER stress tolerance in cell lines with hyper-active mTORC1 signalling. Our initial findings in wild type cells showed nelfinavir inhibited mTORC1 signalling and upregulated autophagy, as determined by decreased rpS6 and S6K1 phosphorylation, and SQTSM1 protein expression, respectively. Contrastingly, cells with hyper-active mTORC1 displayed basally elevated levels of ER stress which was greatly exaggerated following nelfinavir treatment, seen through increased CHOP mRNA and XBP1 splicing. To further enhance the effects of nelfinavir, we introduced chloroquine as an autophagy inhibitor. Combination of nelfinavir and chloroquine significantly increased ER stress and caused selective cell death in multiple cell line models with hyper-active mTORC1, whilst control cells with normalised mTORC1 signalling tolerated treatment. By comparing chloroquine to other autophagy inhibitors, we uncovered that selective toxicity invoked by chloroquine was independent of autophagy inhibition yet entrapment of chloroquine to acidified lysosomal/endosomal compartments was necessary for cytotoxicity. Our research demonstrates that combination of nelfinavir and chloroquine has therapeutic potential for treatment of mTORC1-driven tumours

On the dynamics of the adenylate energy system: homeorhesis vs homeostasis.

Biochemical energy is the fundamental element that maintains both the adequate turnover of the biomolecular structures and the functional metabolic viability of unicellular organisms. The levels of ATP, ADP and AMP reflect roughly the energetic status of the cell, and a precise ratio relating them was proposed by Atkinson as the adenylate energy charge (AEC). Under growth-phase conditions, cells maintain the AEC within narrow physiological values, despite extremely large fluctuations in the adenine nucleotides concentration. Intensive experimental studies have shown that these AEC values are preserved in a wide variety of organisms, both eukaryotes and prokaryotes. Here, to understand some of the functional elements involved in the cellular energy status, we present a computational model conformed by some key essential parts of the adenylate energy system. Specifically, we have considered (I) the main synthesis process of ATP from ADP, (II) the main catalyzed phosphotransfer reaction for interconversion of ATP, ADP and AMP, (III) the enzymatic hydrolysis of ATP yielding ADP, and (IV) the enzymatic hydrolysis of ATP providing AMP. This leads to a dynamic metabolic model (with the form of a delayed differential system) in which the enzymatic rate equations and all the physiological kinetic parameters have been explicitly considered and experimentally tested in vitro. Our central hypothesis is that cells are characterized by changing energy dynamics (homeorhesis). The results show that the AEC presents stable transitions between steady states and periodic oscillations and, in agreement with experimental data these oscillations range within the narrow AEC window. Furthermore, the model shows sustained oscillations in the Gibbs free energy and in the total nucleotide pool. The present study provides a step forward towards the understanding of the fundamental principles and quantitative laws governing the adenylate energy system, which is a fundamental element for unveiling the dynamics of cellular life

Reactive oxygen species and male reproductive hormones

Reports of the increasing incidence of male infertility paired with decreasing semen quality have triggered studies on the effects of lifestyle and environmental factors on the male reproductive potential. There are numerous exogenous and endogenous factors that are able to induce excessive production of reactive oxygen species (ROS) beyond that of cellular antioxidant capacity, thus causing oxidative stress. In turn, oxidative stress negatively affects male reproductive functions and may induce infertility either directly or indirectly by affecting the hypothalamus-pituitary-gonadal (HPG) axis and/or disrupting its crosstalk with other hormonal axes. This review discusses the important exogenous and endogenous factors leading to the generation of ROS in different parts of the male reproductive tract. It also highlights the negative impact of oxidative stress on the regulation and cross-talk between the reproductive hormones. It further describes the mechanism of ROS-induced derangement of male reproductive hormonal profiles that could ultimately lead to male infertility. An understanding of the disruptive effects of ROS on male reproductive hormones would encourage further investigations directed towards the prevention of ROS-mediated hormonal imbalances, which in turn could help in the management of male infertility

Oligometastatic non-small-cell lung cancer: current treatment strategies

Patrick J Richard, Ramesh Rengan Department of Radiation Oncology, University of Washington, Seattle, WA, USA Abstract: The oligometastatic disease theory was initially described in 1995 by Hellman and Weichselbaum. Since then, much work has been performed to investigate its existence in many solid tumors. This has led to subclassifications of stage IV cancer, which could redefine our treatment approaches and the therapeutic outcomes for this historically “incurable” entity. With a high incidence of stage IV disease, non-small-cell lung cancer (NSCLC) remains a difficult cancer to treat and cure. Recent work has proven the existence of an oligometastatic state in NSCLC in terms of properly selecting patients who may benefit from aggressive therapy and experience long-term overall survival. This review discusses the current treatment approaches used in oligometastatic NSCLC and provides the evidence and rationale for each approach. The prognostic factors of many trials are discussed, which can be used to properly select patients for aggressive treatment regimens. Future advances in both molecular profiling of NSCLC to find targetable mutations and investigating patient selection may increase the number of patients diagnosed with oligometastatic NSCLC. As this disease entity increases, it is of utmost importance for oncologists treating NSCLC to be aware of the current treatment strategies that exist and the potential advantages/disadvantages of each. Keywords: oligometastatic, non-small-cell lung cancer, oligoprogressive, treatmen

Self-Assembled Fluorosome-Polydopamine Complex for Efficient Tumor Targeting and Commingled Photodynamic/Photothermal Therapy of Triple-Negative Breast Cancer

Photodynamic/photothermal therapy (PDT/PTT) that deploys a near-infrared responsive nanosystem is emerging to be a promising modality in cancer treatment. It is highly desirable to have a multifunctional nanosystem that can be used for efficient tumor targeting and inhibiting metastasis/recurrence of cancer. In the current study, self-assembled chlorophyll-rich fluorosomes derived fromSpinacia oleraceawere developed. These fluorosomes were co-assembled on a polydopamine core, forming camouflaged nanoparticles (SPoD NPs). The SPoD NPs exhibited a commingled PDT/PTT (i.e., interdependent PTT and PDT) that inhibited both normoxic and hypoxic cancer cell growth. These nanoparticles showed stealth properties with enhanced physiological stability and passive tumor targeting. SPoD NPs also exhibited tumor suppression by synergistic PTT and PDT. It also prevented lung metastasis and splenomegaly in tumor-bearing Balb/c mice. Interestingly, treatment with SPoD NPs also caused the suppression of secondary tumors by eliciting an anti-tumor immune response. In conclusion, a co-assembled multifunctional nanosystem derived fromS. oleraceashowed enhanced stability and tumor-targeting efficacy, resulting in a commingled PDT/PTT effect. © 2021 American Chemical Societ