Positive Effects of Cognitive-Behavioral Therapy Targeting Severe Fatigue Following COVID-19 Are Sustained Up to 1 Year After Treatment
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Kuut, Tanja A. (ORCID:0000000310817025)↗
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Feasibility and preliminary efficacy for morning bright light therapy to improve sleep and plasma biomarkers in US Veterans with TBI. A prospective, open-label, single-arm trial
Mild traumatic brain injury (TBI) is associated with persistent sleep-wake dysfunction, including insomnia and circadian rhythm disruption, which can exacerbate functional outcomes including mood, pain, and quality of life. Present therapies to treat sleep-wake disturbances in those with TBI (e.g., cognitive behavioral therapy for insomnia) are limited by marginal efficacy, poor patient acceptability, and/or high patient/provider burden. Thus, this study aimed to assess the feasibility and preliminary efficacy of morning bright light therapy, to improve sleep in Veterans with TBI (NCT03578003). Thirty-three Veterans with history of TBI were prospectively enrolled in a single-arm, open-label intervention using a lightbox (~10,000 lux at the eye) for 60-minutes every morning for 4-weeks. Pre- and post-intervention outcomes included questionnaires related to sleep, mood, TBI, post-traumatic stress disorder (PTSD), and pain; wrist actigraphy as a proxy for objective sleep; and blood-based biomarkers related to TBI/sleep. The protocol was rated favorably by ~75% of participants, with adherence to the lightbox and actigraphy being ~87% and 97%, respectively. Post-intervention improvements were observed in self-reported symptoms related to insomnia, mood, and pain; actigraphy-derived measures of sleep; and blood-based biomarkers related to peripheral inflammatory balance. The severity of comorbid PTSD was a significant positive predictor of response to treatment. Morning bright light therapy is a feasible and acceptable intervention that shows preliminary efficacy to treat disrupted sleep in Veterans with TBI. A full-scale randomized, placebo-controlled study with longitudinal follow-up is warranted to assess the efficacy of morning bright light therapy to improve sleep, biomarkers, and other TBI related symptoms.
60 APPLIED LIFE SCIENCES↗
p -Azaquinodimethane: A Versatile Quinoidal Moiety for Functional Materials Discovery
The past 50 years of discovery in organic electronics have been driven in large part by the donor–acceptor design principle, wherein electron-rich and electron-poor units are assembled in conjugation with each other to produce small band gap materials. While the utility of this design strategy is undoubtable, it has been largely exhausted as a frontier of new avenues to produce and tune novel functional materials to meet the needs of the ever-increasing world of organic electronics applications. Its sister strategy of joining quinoidal and aromatic groups in conjugation has, by comparison, received much less attention, to a great extent due to the categorically poor stability of quinoidal conjugated motifs. In 2017 though, the p-azaquinodimethane (AQM) motif was first unveiled, which showed a remarkable level of stability despite being a close structural analogue to p-quinodimethane, a notably reactive compound. In contrast, dialkoxy AQM small molecules and polymers are stable even under harsh conditions and could thus be incorporated into conjugated polymers. When polymerized with aromatic subunits, these AQM-based polymers show notably reduced band gaps that follow reversed structure–property trends to some of their donor–acceptor polymer counterparts and yield organic field-effect transistor (OFET) hole mobilities above 5 cm 2 V –1 s –1 . Additionally, in an ongoing study, these AQM-based compounds are also showing promise as singlet fission (SF) active materials due to their mild diradicaloid character. An expanded world of AQMs was accessed through their ditriflate derivatives, which were first used to produce ionic AQMs (iAQMs) sporting two directly attached cationic groups that significantly affect the AQM motif’s electronics, producing strongly electron-withdrawing quinoidal building blocks. Conjugated polyelectrolytes (CPEs) created with these iAQM building blocks exhibit optical band gaps stretching into the near-infrared I (NIR-I) region and showed exemplary behavior as photothermal therapy agents. In contrast to these stable AQM examples, the synthetic exploration of AQMs also produced examples of more typical diradicaloid reactivity but in forms that were controllable and produced intriguing and high-value products. With certain substitution patterns, AQMs were found to dimerize to form highly substituted [2.2]paracyclophanes in distinctly more appreciable yields than typical cyclophane formation reactions. Certain AQM ditriflates, when crystallized, undergo light-induced topochemical polymerization to form ultrahigh molecular weight (>10 6 Da) polymers that showed excellent performances as dielectric energy storage materials. These same AQM ditriflates could be used to produce the strongly electron-donating redox-active pentacyclic structure: pyrazino[2,3-b:5,6-b']diindolizine (PDIz). Importantly, the PDIz motif allowed for the synthesis of exceedingly small band gap (0.7 eV) polymers with absorbances reaching all the way into the NIR-II region that were also found to produce strong photothermal effects. Both as stable quinoidal building blocks and through their controllable diradicaloid reactivity, AQMs have already proven to be versatile and effective as functional organic electronics materials.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Uptake and Binding of At‐211 Into K‐ and Cs‐Derivatives of Alpha‐Zirconium Phosphate Nanoplatelets for Use as a Targeted Alpha Therapy Delivery Platform
The ion exchange behavior of K- and Cs-derivatives of α-zirconium phosphate, A-ZrP, with the targeted alpha therapy (TAT) radionuclide 211 At, as At + and AtO + , has been investigated. The K-ZrP shows strong affinity for both At+ and AtO + , ≥99% uptake. The affinity to Cs-ZrP was less pronounced, 87%–94% uptake, favoring At + . The binding strength was tested against several leaching solutions, including carbonate, phosphate buffered saline (PBS), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffers, and ethylenediaminetetraacetic acid (EDTA) solutions at various concentrations (0.1–10 mM). K-ZrP retained 211 At in all buffer and EDTA solutions up to 1 mM (<0.5% leaching). The Cs-ZrP showed no leaching of At + , while AtO + leached (1%–3%) in the carbonate and HEPES buffers, along with all of the EDTA solutions, with complete retention only in the PBS buffer. In all cases, when the EDTA concentration reached 10 mM, 211 At leaching was observed. Once incorporated into the ZrP nanoplatelets, significant shielding of the α-particles was observed, not only attenuating the intensity of the emission but also reducing the energy of the α-particles themselves exiting the nanoplatelets. These properties provide the basis for K-ZrP, and to a lesser extent, Cs-ZrP to be further considered as potentially promising candidates for a delivery mechanism of 211 At for application in TAT.
astatine-211↗
Preclinical tumor organoid models in personalized cancer therapy: Not everyone fits the mold
Highlights: • In personalized cancer medicine, each patient receives a specific treatment. • The tumor microenvironment and interpersonal differences can affect treatment. • Organoid culture systems fully recapitulate the tumor microenvironments. In contrast to conventional cancer treatment, in personalized cancer medicine each patient receives a specific treatment. The response to therapy, clinical outcomes, and tumor behavior such as metastases, tumor progression, carcinogenesis can be significantly affected by the heterogeneous tumor microenvironment (TME) and interpersonal differences. Therefore, using native tumor microenvironment mimicking models is necessary to improving personalized cancer therapy. Both in vitro 2D cell culture and in vivo animal models poorly recapitulate the heterogeneous tumor (immune) microenvironments of native tumors. The development of 3D culture models, native tumor microenvironment mimicking models, made it possible to evaluate the chemoresistance of tumor tissue and the functionality of drugs in the presence of cell-extracellular matrix and cell-cell interactions in a 3D construction. Various personalized tumor models have been designed to preserving the native tumor microenvironment, including patient-derived tumor xenografts and organoid culture strategies. In this review, we will discuss the patient-derived organoids as a native tumor microenvironment mimicking model in personalized cancer therapy. In addition, we will also review the potential and the limitations of organoid culture systems for predicting patient outcomes and preclinical drug screening. Finally, we will discuss immunotherapy drug screening in tumor organoids by using microfluidic technology.
60 APPLIED LIFE SCIENCES↗
Behavioral Determinants of Canadian Radiation Oncologists’ Use of Single Fraction Palliative Radiation Therapy for Uncomplicated Bone Metastases
A mainstay therapy for pain relief from uncomplicated bone metastases is external beam radiation therapy. Single fraction radiation therapy (SFRT) is more convenient and cost-effective, causes fewer acute side effects, and is equivalent to multiple fraction radiation therapy for pain relief. Despite these advantages, radiation oncologists seldom prescribe SFRT.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Allopregnanolone as an Adjunct Therapy to Midazolam is More Effective Than Midazolam Alone in Suppressing Soman‐Induced Status Epilepticus in Male Rats
ABSTRACT Aims Humans and animals acutely intoxicated with the organophosphate soman can develop sustained status epilepticus (SE) that rapidly becomes refractory to benzodiazepines. We compared the antiseizure efficacy of midazolam, a current standard of care treatment for OP‐induced SE, versus combined therapy with midazolam and allopregnanolone (ALLO) in a rat model of soman‐induced SE. Methods Soman‐intoxicated male rats with robust seizure behavior and high‐amplitude electroencephalographic (EEG) activity were administered midazolam (0.65 mg, i.m.) 20 min after seizure initiation and 10 min later either a second dose of midazolam or ALLO (12 or 24 mg/kg, i.m.). Seizure behavior and EEG were monitored for 4 h after treatment. Brains were collected at the end of the monitoring period for histological analyses. Results Animals receiving 2 doses of midazolam exhibited persistent SE. Sequential dosing with midazolam followed by ALLO suppressed electrographic seizure activity. The combination therapy also significantly reduced soman‐induced neurodegeneration and neuroinflammation compared to 2 doses of midazolam. High but not low dose ALLO was associated with transitory and reversible respiratory compromise during the 1 h period after dosing. Conclusions Treatment with midazolam followed by ALLO was more effective than 2 doses of midazolam in suppressing benzodiazepine‐refractory, soman‐induced SE, and in mitigating its acute neuropathological consequences.
Andrew, Peter M. [Department of Molecular Bioscien↗
Emerging roles of circular RNAs in thyroid cancer
As the most common endocrine-related malignant tumor, the prevalence of thyroid cancer (TC) has soared strikingly over the past thirty years then verged to stabilization or even descension temporally. Distributed in a cell-specific manner, circular RNAs (circRNAs) is a novel class of non-coding RNAs characterized by its covalently closed loop without 5′-terminal cap and 3′-terminal poly A tail, which guarantee its distinctive evolutionary conservation and exonucleases resistance. Emerging evidence indicates that circRNA participates in the pathogenesis and carcinogenesis of several cancers including thyroid cancer. In this review, we concentrated on the connection between circRNAs and thyroid cancer so as to obtain a more profound understanding. We aim to discuss this relationship between TC and circRNAs by summarizing the effect of various circRNAs on tumor biological behaviors and clinical application, and systematically outlook the conceivable application of circRNAs in TC diagnosis and therapy.
60 APPLIED LIFE SCIENCES↗
Vascular endothelial and smooth muscle cell galvanotactic response and differential migratory behavior
Chronic disease or injury of the vasculature impairs the functionality of vascular wall cells particularly in their ability to migrate and repair vascular surfaces. Under pathologic conditions, vascular endothelial cells (ECs) lose their non-thrombogenic properties and decrease their motility. Alternatively, vascular smooth muscle cells (SMCs) may increase motility and proliferation, leading to blood vessel luminal invasion. Current therapies to prevent subsequent blood vessel occlusion commonly mechanically injure vascular cells leading to endothelial denudation and smooth muscle cell luminal migration. Due to this dichotomous migratory behavior, a need exists for modulating vascular cell growth and migration in a more targeted manner. Here, we examine the efficacy of utilizing small direct current electric fields to influence vascular cell-specific migration (“galvanotaxis”). We designed, fabricated, and implemented an in vitro chamber for tracking vascular cell migration direction, distance, and displacement under galvanotactic influence of varying magnitude. Our results indicate that vascular ECs and SMCs have differing responses to galvanotaxis; ECs exhibit a positive correlation of anodal migration while SMCs exhibit minimal change in directional migration in relation to the electric field direction. SMCs exhibit less motility response (i.e. distance traveled in 4 h) compared to ECs, but SMCs show a significantly higher motility at low electric potentials (80 mV/cm). With further investigation and translation, galvanotaxis may be an effective solution for modulation of vascular cell-specific migration, leading to enhanced endothelialization, with coordinate reduced smooth muscle in-migration.
60 APPLIED LIFE SCIENCES↗
Heavy Ion Minibeam Therapy: Side Effects in Normal Brain
The purpose of this work was to investigate whether minibeam therapy with heavy ions might offer improvements of the therapeutic ratio for the treatment of human brain cancers. To assess neurotoxicity, we irradiated normal juvenile rats using 120 MeV lithium-7 ions at an absorbed integral dose of 20 Gy. Beams were configured either as a solid parallel circular beam or as an array of planar parallel minibeams having 300-micron width and 1-mm center-to-center spacing within a circular array. We followed animals for 6 months after treatment and utilized behavioral testing and immunohistochemical studies to investigate the resulting cognitive impairment and chronic pathologic changes. We found both solid-beam therapy and minibeam therapy to result in cognitive impairment compared with sham controls, with no apparent reduction in neurotoxicity using heavy ion minibeams instead of solid beams under the conditions of this study.
60 APPLIED LIFE SCIENCES↗
Structures of HIV-1 Neutralizing Antibody 10E8 Delineate the Mechanistic Basis of Its Multi-Peak Behavior on Size-Exclusion Chromatography
Antibody 10E8 is capable of effectively neutralizing HIV through its recognition of the membrane-proximal external region (MPER), and a suitably optimized version of 10E8 might have utility in HIV therapy and prophylaxis. However, 10E8 displays a three-peak profile on size-exclusion chromatography (SEC), complicating its manufacture. Here we show cis-trans conformational isomerization of the Tyr-Pro-Pro (YPP) motif in the heavy chain 3rd complementarity-determining region (CDR H3) of antibody 10E8 to be the mechanistic basis of its multipeak behavior. We observed 10E8 to undergo slow conformational isomerization and delineate a mechanistic explanation for effective comodifiers that were able to resolve its SEC heterogeneity and to allow an evaluation of the critical quality attribute of aggregation. We determined crystal structures of single and double alanine mutants of a key di-proline motif and of a light chain variant, revealing alternative conformations of the CDR H3. We also replicated both multi-peak and delayed SEC behavior with MPER-antibodies 4E10 and VRC42, by introducing a Tyr-Pro (YP) motif into their CDR H3s. Our results show how a conformationally dynamic CDR H3 can provide the requisite structural plasticity needed for a highly hydrophobic paratope to recognize its membrane-proximal epitope.
60 APPLIED LIFE SCIENCES↗
A Solid-State Support for Separating Astatine-211 from Bismuth
Increasing access to the short-lived α-emitting radionuclide astatine-211 ( 211 At) has the potential to advance targeted α-therapeutic treatment of disease and to solve challenges facing the medical community. For example, there are numerous technical needs associated with advancing the use of 211 At in targeted α-therapy, e.g., improving 211 At chelates, developing more effective 211 At targeting, and characterizing in vivo 211 At behavior. There is an insufficient understanding of astatine chemistry to support these efforts. The chemistry of astatine is one of the least developed of all elements on the periodic table, owing to its limited supply and short half-life. Increasing access to 211 At could help address these issues and advance understanding of 211 At chemistry in general. Here, we contribute an extraction chromatographic processing method that simplifies 211 At production in terms of purification. It utilizes the commercially available Pre-Filter resin to rapidly (<1.5 h) isolate 211 At from irradiated bismuth targets (Bi decontamination factors ≥876 000), in reasonable yield (68–55%) and in a form that is compatible for subsequent in vivo study. We are excited about the potential of this procedure to address 211 At supply and processing/purification problems.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
The electron affinity of astatine
One of the most important properties influencing the chemical behavior of an element is the electron affinity (EA). Among the remaining elements with unknown EA is astatine, where one of its isotopes, 211 At, is remarkably well suited for targeted radionuclide therapy of cancer. With the At - anion being involved in many aspects of current astatine labeling protocols, the knowledge of the electron affinity of this element is of prime importance. Here we report the measured value of the EA of astatine to be 2.41578(7) eV. This result is compared to state-of-the-art relativistic quantum mechanical calculations that incorporate both the Breit and the quantum electrodynamics (QED) corrections and the electron–electron correlation effects on the highest level that can be currently achieved for many-electron systems. The developed technique of laser-photo detachment spectroscopy of radioisotopes opens the path for future EA measurements of other radioelements such as polonium, and eventually super-heavy elements.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
FLASH-therapy suitable single-pulse proton generation using TiH 2 under nanosecond laser irradiation
We investigated proton emission from titanium hydride (TiH 2 ) targets irradiated in vacuum by a 6-ns, 1064-nm Nd:YAG laser. Time-of-flight measurements with a Faraday cup and an electrostatic ion analyzer resolved distinct proton peaks at high pulse energies, with yields on the order of 10 9 protons per shot. Systematic scans over pulse energy and up to 1000 repeated shots showed that, while the peak amplitude gradually decreased, the integrated proton number remained nearly constant. This behavior is consistent with surface-induced broadening of the plasma expansion while bulk hydrogen is replenished by diffusion and repeated ablation of fresh TiH 2 layers. Using the measured proton numbers and pulse widths, a simple direct-plasma-injection-style scaling indicates peak currents of ∼100 mA and sub-microsecond pulse durations. The pulse structure and yield satisfy key ultra-high-dose-rate criteria and, together with sustained output over 1000 shots, support TiH 2 -based laser ion sources as practical candidates for FLASH-therapy (ultra-high-dose-rate)-oriented studies and injector development using direct plasma injection.
43 PARTICLE ACCELERATORS↗
Analysis of tumor-immune functional responses in a mathematical model of neoantigen cancer vaccines
Cancer neoantigen vaccines have emerged as a promising approach to stimulating the immune system to fight cancer. We propose a simple model including key elements of cancer-immune interactions and conduct a phase plane analysis to understand the immunological mechanisms of cancer neoantigen vaccines. Analytical results are obtained for two widely used functional forms that represent the killing rate of tumor cells by immune cells: the law of mass action (LMA) and the dePillis-Radunskaya Law (LPR). Using the LMA, our results reveal that a slowly growing tumor can escape the immune surveillance and that there is a unique periodic solution. The LPR offers richer dynamics, in which tumor elimination and uncontrolled tumor growth are both present. We show that tumor elimination requires sufficient number of initial activated T cells in relationship to the malignant cells, which lends support to using the neoantigen cancer vaccine as an adjuvant therapy after the primary tumor is surgically removed or treated using radiotherapy. We also derive a sufficient condition for uncontrolled tumor growth under the assumption of the LPR. Here, the juxtaposition of analyses with these two different choices for the killing rate function highlights their importance on model behavior and biological implications, by which we hope to spur further theoretical and experimental work to understand mechanisms underlying different functional forms for the killing rate.
60 APPLIED LIFE SCIENCES↗
Structural basis for antibody recognition of the proximal MUC16 ectodomain
Mucin 16 (MUC16) overexpression is linked with cancer progression, metastasis, and therapy resistance in high grade serous ovarian cancer and other malignancies. The cleavage of MUC16 forms independent bimodular fragments, the shed tandem repeat sequence which circulates as a protein bearing the ovarian cancer biomarker (CA125) and a proximal membrane-bound component which is critical in MUC16 oncogenic behavior. A humanized, high affinity antibody targeting the proximal ectodomain represents a potential therapeutic agent against MUC16 with lower antigenic potential and restricted human tissue expression. Here, we demonstrate the potential therapeutic versatility of the humanized antibody as a monoclonal antibody, antibody drug conjugate, and chimeric antigen receptor. We report the crystal structures of 4H11-scFv, derived from an antibody specifically targeting the MUC16 C-terminal region, alone and in complex with a 26-amino acid MUC16 segment resolved at 2.36 Å and 2.47 Å resolution, respectively. The scFv forms a robust interaction with an epitope consisting of two consecutive β-turns and a β-hairpin stabilized by 2 hydrogen bonds. The V H -V L interface within the 4H11-scFv is stabilized through an intricate network of 11 hydrogen bonds and a cation-π interaction. Together, our studies offer insight into antibody-MUC16 ectodomain interaction and advance our ability to design agents with potentially improved therapeutic properties over anti-CA125 moiety antibodies.
60 APPLIED LIFE SCIENCES↗
The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View
The collection of microbes that live in and on the human body – the human microbiome – can impact on cancer initiation, progression, and response to therapy, including cancer immunotherapy. The mechanisms by which microbiomes impact on cancers can yield new diagnostics and treatments, but much remains unknown. The interactions between microbes, diet, host factors, drugs, and cell–cell interactions within the cancer itself likely involve intricate feedbacks, and no single component can explain all the behavior of the system. Understanding the role of host-associated microbial communities in cancer systems will require a multidisciplinary approach combining microbial ecology, immunology, cancer cell biology, and computational biology – a systems biology approach.
Xavier, Joao B.↗
Modeling hepatitis C micro-elimination among people who inject drugs with direct-acting antivirals in metropolitan Chicago
Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and mortality worldwide. Direct-acting antiviral (DAA) therapy leads to high cure rates. However, persons who inject drugs (PWID) are at risk for reinfection after cure and may require multiple DAA treatments to reach the World Health Organization’s (WHO) goal of HCV elimination by 2030. Using an agent-based model (ABM) that accounts for the complex interplay of demographic factors, risk behaviors, social networks, and geographic location for HCV transmission among PWID, we examined the combination(s) of DAA enrollment (2.5%, 5%, 7.5%, 10%), adherence (60%, 70%, 80%, 90%) and frequency of DAA treatment courses needed to achieve the WHO’s goal of reducing incident chronic infections by 90% by 2030 among a large population of PWID from Chicago, IL and surrounding suburbs. We also estimated the economic DAA costs associated with each scenario. Our results indicate that a DAA treatment rate of >7.5% per year with 90% adherence results in 75% of enrolled PWID requiring only a single DAA course; however 19% would require 2 courses, 5%, 3 courses and <2%, 4 courses, with an overall DAA cost of $325 million to achieve the WHO goal in metropolitan Chicago. We estimate a 28% increase in the overall DAA cost under low adherence (70%) compared to high adherence (90%). Our modeling results have important public health implications for HCV elimination among U.S. PWID. Using a range of feasible treatment enrollment and adherence rates, we report robust findings supporting the need to address re-exposure and reinfection among PWID to reduce HCV incidence.
60 APPLIED LIFE SCIENCES↗