Modulations of ferroptosis in lung cancer therapy.

INTRODUCTION: Ferroptosis is iron-dependent regulated cell death and is a field of research that has been rapidly growing in recent years. Many preclinical studies show therapeutic benefit of ferroptosis modulation in lung cancers. There are advancements using prognostic ferroptosis-related genes to directly predict outcomes in lung cancer. Targeted therapy using RNA and nanoparticle technology have also shown benefits in ferroptosis induction. Currently, there is limited comprehensive evaluation of how ferroptosis can be used in lung cancer therapy. Thus, the aim of this report is to build an overview of all data on ferroptosis modulation in lung cancer. AREAS COVERED: Ferroptotic cell death mechanisms and how ferroptosis is highly distinguished from other forms of cell death, offered insight on the modulations of ferroptosis in killing lung cancer cells in preclinical studies. Search databases included PubMed, Google scholar, and clinicaltrials.gov through the last 10 years. EXPERT OPINION: Ferroptosis modulation in lung cancer is a promising therapeutic option, but greater understanding and progression from primarily in vitro studies to animal studies and clinical trials is needed to substantiate its utilization in practice. Future strategies of using ferroptosis modulation adjuvant to first-line therapy may increase its effectiveness and overcome apoptosis-resistance cancers.

Retrospective study demonstrating therapy time impact on inpatient rehabilitation functional gains.

PURPOSE: The purpose of this retrospective study is to evaluate the association of total therapy time during inpatient rehabilitation and gain in functional independence for patients admitted to an inpatient rehabilitation facility (IRF). MATERIALS AND METHODS: The study utilized a retrospective design that included all IRF patients from three IRFs in California from January 1, 2012 to December 31, 2013. Patient data collected as part of usual, routine medical, and rehabilitation care were used and includes demographics, medical variables, and functional outcomes data. RESULTS: There were 3212 patients discharged from the three IRFs, with 2,777 patients having received speech language pathology (SLP) therapy along with occupational therapy and physical therapy. Speech language pathology services were not provided for 435 patients in the database. Our results support that among all types of patients, increased therapy hours were associated with increased functional gains. For total functional independence measure (FIM) gain, an additional hour of PT therapy per day was associated with an increase of 7.55 FIM gain points (p < 0.001) and an additional hour of OT therapy per day was associated with an increase of 1.16 FIM gain points (p = 0.045), when adjusted for other variables in the model. SLP hours per day did not remain in the FIM gain model. CONCLUSIONS: The findings of this study add to the understanding of therapy time and functional gain in an inpatient rehabilitation program. There is a positive relationship between total therapy time and functional gain. In the future determining the intensity and the related therapy activities provided will be needed to impact functional change. This has implications for shaping rehabilitation practice in the future.Implications for rehabilitationIncreased number of therapy hours were associated with functional gains in an inpatient rehabilitation program for all types of patients.An additional hour of physical therapy per day was associated with an increase of 7.55 functional independence measure (FIM) point gain.An additional hour of occupational therapy per day was associated with an increase of 1.16 FIM point gain.Determining the intensity and related activities are needed to impact functional change which has implications for shaping rehabilitation practice.

PTSD symptoms are associated with visual retrieval performance in OEF/OIF/OND veterans.

Posttraumatic stress disorder (PTSD) is associated with poorer performance on neuropsychological tests in veterans. However, prior studies have generally compared individuals with PTSD to control groups, often excluding individuals with moderate symptoms. The present study evaluated neuropsychological performance among OEF/OIF/OND veterans as a function of overall PTSD severity, while also exploring potential associations between cognitive performance and PTSD symptom clusters. Using a brief neuropsychological battery, clinical interviews, and self-report instruments, we evaluated neuropsychological and psychiatric functioning in 90 OEF/OIF/OND veterans. When controlling for the effects of premorbid intellectual functioning and combat exposure, higher PTSD severity predicted worse visual retrieval performance, but not attention, verbal retrieval, visual learning, or executive functioning performance. A trend was observed where higher PTSD symptoms predicted worse verbal learning performance. All PTSD symptom clusters were associated with visual retrieval performance within the full sample. Avoidance and numbing symptoms were associated with verbal learning in the full sample. Findings suggest that among OEF/OIF/OND veterans with a range of PTSD symptoms, the assessment of visual memory may have implications for clinical practice.

Imaging Atomic-Scale Clustering in III-V Semiconductor Alloys.

Quaternary alloys are essential for the development of high-performance optoelectronic devices. However, immiscibility of the constituent elements can make these materials vulnerable to phase segregation, which degrades the optical and electrical properties of the solid. High-efficiency III-V photovoltaic cells are particularly sensitive to this degradation. InAlAsSb lattice matched to InP is a promising candidate material for high-bandgap subcells of a multijunction photovoltaic device. However, previous studies of this material have identified characteristic signatures of compositional variation, including anomalous low-energy photoluminescence. In this work, atomic-scale clustering is observed in InAlAsSb via quantitative scanning transmission electron microscopy. Image quantification of atomic column intensity ratios enables the comparison with simulated images, confirming the presence of nonrandom compositional variation in this multispecies alloy.

Herbicides and trace metals in urban waters in Melbourne, Australia (2011-12): concentrations and potential impact.

Urban stormwater samples were collected from five aquatic systems in Melbourne, Australia, on six occasions between October 2011 and March 2012 and tested for 30 herbicides and 14 trace metals. Nineteen different herbicides were observed in one or more water samples from the five sites; chemicals observed at more than 40% of sites were simazine (100%), MCPA (83%), diuron (63%) and atrazine (53%). Using the toxicity unit (TU) concept to assess potential risk to aquatic ecosystems, none of the detected herbicides were considered to pose an individual, group or collective short-term risk to fish or zooplankton in the waters studied. However, 13 herbicides had TU values suggesting they might have posed an individual risk to primary producers at the time of sampling. Water quality guideline levels were exceeded on many occasions for Cd, Cu, Cr, Pb and Zn. Similarly, RQmed and RQmax exceeded 1 for Cd, Cr, Cu, Mn, Ni, Pb, V and Zn. Almost all the metals screened exceeded a log10TU of -3 for every trophic level, suggesting that there may have been some impact on aquatic organisms in the studied waterbodies. Our data indicate that Melbourne's urban aquatic environments may be being impacted by approved domestic, industrial and sporting application of herbicides and that stormwater quality needs to be carefully assessed prior to reuse. Further research is required to understand the performance of different urban stormwater wetland designs in removing pesticides and trace metals. Applying the precautionary principle to herbicide regulation is important to ensure there is more research and assessment of the long-term 'performance' standard of all herbicides and throughout their 'life cycle'. Implementing such an approach will also ensure government, regulators, decision makers, researchers, policy makers and industry have the best possible information available to improve the management of chemicals, from manufacture to use.

Affective and cognitive correlates of PTSD: Electrocortical processing of threat and perseverative errors on the WCST in combat-related PTSD.

PTSD is characterized by both affective and cognitive dysfunction. Affectively, PTSD is associated with both heightened emotional reactivity and disengagement. Cognitively, perseverative thinking is a core feature of the disorder. In order to assess the interactive effects of affective and cognitive correlates of PTSD symptoms, 47 OEF/OIF/OND veterans completed an emotional faces matching task while EEG (i.e., late positive potential; LPP) was recorded, and separately completed the Wisconsin Card Sorting Test (WCST) to assess perseverative errors. There was no relationship between PTSD symptoms and either perseverative errors or EEG reactivity to faces. However, an interaction was found such that high perseverative errors on the WCST and a relatively enhanced LPP to angry faces was associated with greater PTSD symptoms, while low errors on the WCST and a relatively blunted LPP to angry faces also related to greater PTSD symptoms. These findings suggest that emotion-cognition interactions are important for understanding PTSD, and that distinct emotion-cognition constellations interact with symptoms.

Identification of NAD+ capped mRNAs in Saccharomyces cerevisiae.

RNAs besides tRNA and rRNA contain chemical modifications, including the recently described 5' nicotinamide-adenine dinucleotide (NAD+) RNA in bacteria. Whether 5' NAD-RNA exists in eukaryotes remains unknown. We demonstrate that 5' NAD-RNA is found on subsets of nuclear and mitochondrial encoded mRNAs in Saccharomyces cerevisiae NAD-mRNA appears to be produced cotranscriptionally because NAD-RNA is also found on pre-mRNAs, and only on mitochondrial transcripts that are not 5' end processed. These results define an additional 5' RNA cap structure in eukaryotes and raise the possibility that this 5' NAD+ cap could modulate RNA stability and translation on specific subclasses of mRNAs.

Impact of alcohol use disorder comorbidity on defensive reactivity to errors in veterans with posttraumatic stress disorder.

Converging lines of evidence suggest that individuals with comorbid posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) may be characterized by heightened defensive reactivity, which serves to maintain drinking behaviors and anxiety/hyperarousal symptoms. However, it is important to note that very few studies have directly tested whether individuals with PTSD and AUD exhibit greater defensive reactivity compared with individuals with PTSD without AUD. Therefore, the aim of the current study was to test this emerging hypothesis by examining individual differences in error-related negativity (ERN), an event-related component that is larger among anxious individuals and is thought to reflect defensive reactivity to errors. Participants were 66 military veterans who completed a well-validated flanker task known to robustly elicit the ERN. Veterans were comprised of 3 groups: controls (i.e., no PTSD or AUD), PTSD-AUD (i.e., current PTSD but no AUD), and PTSD + AUD (i.e., current comorbid PTSD and AUD). Results indicated that individuals with PTSD and controls generally did not differ in ERN amplitude. However, among individuals with PTSD, those with comorbid AUD had significantly larger ERNs than those without AUD. These findings suggest that PTSD + AUD is a neurobiologically unique subtype of PTSD, and the comorbidity of AUD may enhance defensive reactivity to errors in individuals with PTSD. (PsycINFO Database Record

Frontal lobe regulation of blood glucose levels: support for the limited capacity model in hostile violence-prone men.

Hostile men have reliably displayed an exaggerated sympathetic stress response across multiple experimental settings, with cardiovascular reactivity for blood pressure and heart rate concurrent with lateralized right frontal lobe stress (Trajanoski et al., in Diabetes Care 19(12):1412-1415, 1996; see Heilman et al., in J Neurol Neurosurg Psychiatry 38(1):69-72, 1975). The current experiment examined frontal lobe regulatory control of glucose in high and low hostile men with concurrent left frontal lobe (Control Oral Word Association Test [verbal]) or right frontal lobe (Ruff Figural Fluency Test [nonverbal]) stress. A significant interaction was found for Group × Condition, F (1,22) = 4.16, p ≤ .05 with glucose levels (mg/dl) of high hostile men significantly elevated as a function of the right frontal stressor (M = 101.37, SD = 13.75) when compared to the verbal stressor (M = 95.79, SD = 11.20). Glucose levels in the low hostile group remained stable for both types of stress. High hostile men made significantly more errors on the right frontal but not the left frontal stressor (M = 17.18, SD = 19.88) when compared to the low hostile men (M = 5.81, SD = 4.33). These findings support our existing frontal capacity model of hostility (Iribarren et al., in J Am Med Assoc 17(19):2546-2551, 2000; McCrimmon et al., in Physiol Behav 67(1):35-39, 1999; Brunner et al., in Diabetes Care 21(4):585-590, 1998), extending the role of the right frontal lobe to regulatory control over glucose mobilization.

Feasibility of Canine Therapy Among Hospitalized Pre-Heart Transplant Patients.

OBJECTIVES: Canine-assisted therapy (CAT) has been used in many settings with much success, yet no study has assessed its feasibility and receptiveness in hospitalized patients awaiting heart transplantation. METHODS: Patients admitted to our institution with a status I for heart transplantation during a 12-month period (April 2014-April 2015) were prospectively included in a feasibility pilot study. Patients were included if there was no history of transmittable disease or active infectious process and consented for study participation. Each patient was visited daily by a canine and quantitative and qualitative data regarding the visit were obtained. RESULTS: A total of 11 patients were included in the study. Most patients were men (n = 8, 72.7%) and the average age was 51.1 years. A total of 146 individual therapies took place, totaling 2718 minutes of CAT during the study period. Each patient had an average of 13.3 visits and each visit had an average duration of 14.7 minutes. Patient receptiveness, as measured by the CAT volunteer, averaged 9.9 (scale 0-10). No reports of infection transmission occurred. CONCLUSIONS: Our study found that CAT among hospitalized pre-heart transplant patients is feasible and is a welcomed adjunct to usual medical care.

ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure.

Stress granules are mRNA-protein granules that form when translation initiation is limited, and they are related to pathological granules in various neurodegenerative diseases. Super-resolution microscopy reveals stable substructures, referred to as cores, within stress granules that can be purified. Proteomic analysis of stress granule cores reveals a dense network of protein-protein interactions and links between stress granules and human diseases and identifies ATP-dependent helicases and protein remodelers as conserved stress granule components. ATP is required for stress granule assembly and dynamics. Moreover, multiple ATP-driven machines affect stress granules differently, with the CCT complex inhibiting stress granule assembly, while the MCM and RVB complexes promote stress granule persistence. Our observations suggest that stress granules contain a stable core structure surrounded by a dynamic shell with assembly, disassembly, and transitions between the core and shell modulated by numerous protein and RNA remodeling complexes.

Pesticide and trace metals in surface waters and sediments of rivers entering the Corner Inlet Marine National Park, Victoria, Australia.

Water and sediment samples were collected from up to 17 sites in waterways entering the Corner Inlet Marine National Park monthly between November 2009 and April 2010, with the Chemcatcher passive sampler system deployed at these sites in November 2009 and March 2010. Trace metal concentrations were low, with none occurring at concentrations with the potential for adverse ecological effects. The agrochemical residues data showed the presence of a small number of pesticides at very low concentration (ng/L) in the surface waters of streams entering the Corner Inlet, and as widespread, but still limited contamination of sediments. Concentrations of pesticides detected were relatively low and several orders of magnitude below reported ecotoxicological effect and hazardous concentration values. The low levels of pesticides detected in this study indicate that agricultural industries were responsible agrochemical users. This research project is a rarity in aligning both agrochemical usage data obtained from chemical resellers in the target catchment with residue analysis of environmental samples. Based on frequency of detection and concentrations, prometryn is the priority chemical of concern for both the water and sediments studied, but this chemical was not listed in reseller data. Consequently, the risks may be greater than the field data would suggest, and priorities for monitoring different since some commonly used herbicides (such as glyphosate, phenoxy acid herbicides, and sulfonyl urea herbicides) were not screened. Therefore, researchers, academia, industry, and government need to identify ways to achieve a more coordinated land use approach for obtaining information on the use of chemicals in a catchment, their presence in waterways, and the longer term performance of chemicals, particularly where they are used multiple times in a year.

Coupling of Ribostasis and Proteostasis: Hsp70 Proteins in mRNA Metabolism.

A key aspect of the control of gene expression is the differential rates of mRNA translation and degradation, including alterations due to extracellular inputs. Surprisingly, multiple examples now argue that Hsp70 protein chaperones and their associated Hsp40 partners modulate both mRNA degradation and translation. Hsp70 proteins affect mRNA metabolism by various mechanisms including regulating nascent polypeptide chain folding, activating signal transduction pathways, promoting clearance of stress granules, and controlling mRNA degradation in an mRNA-specific manner. Taken together, these observations highlight the general principle that mRNA metabolism is coupled to the proteostatic state of the cell, often as assessed by the presence of unfolded or misfolded proteins.

Differential effects of Ydj1 and Sis1 on Hsp70-mediated clearance of stress granules in Saccharomyces cerevisiae.

Stress granules and P-bodies are conserved assemblies of nontranslating mRNAs in eukaryotic cells that can be related to RNA-protein aggregates found in some neurodegenerative diseases. Herein, we examine how the Hsp70/Hsp40 protein chaperones affected the assembly and disassembly of stress granules and P-bodies in yeast. We observed that Hsp70 and the Ydj1 and Sis1 Hsp40 proteins accumulated in stress granules and defects in these proteins led to decreases in the disassembly and/or clearance of stress granules. We observed that individual Hsp40 proteins have different effects on stress granules with defects in Ydj1 leading to accumulation of stress granules in the vacuole and limited recovery of translation following stress, which suggests that Ydj1 promotes disassembly of stress granules to promote translation. In contrast, defects in Sis1 did not affect recovery of translation, accumulated cytoplasmic stress granules, and showed reductions in the targeting of stress granules to the vacuole. This demonstrates a new principle whereby alternative disassembly machineries lead to different fates of components within stress granules, thereby providing additional avenues for regulation of their assembly, composition, and function. Moreover, a role for Hsp70 and Hsp40 proteins in stress granule disassembly couples the assembly of these stress responsive structures to the proteostatic state of the cell.

Next generation drying technologies for pharmaceutical applications.

Drying is a commonly used technique for improving the product stability of biotherapeutics. Typically, drying is accomplished through freeze-drying, as evidenced by the availability of several lyophilized products on the market. There are, however, a number of drawbacks to lyophilization, including the lengthy process time required for drying, low energy efficiency, high cost of purchasing and maintaining the equipment, and sensitivity of the product to freezing and various other processing-related stresses. These limitations have led to the search for next-generation drying methods that can be applied to biotherapeutics. Several alternative drying methods are reviewed herein, with particular emphasis on methods that are commonly employed outside of the biopharmaceutical industry including spray drying, convective drying, vacuum drying, microwave drying, and combinations thereof. Although some of the technologies have already been implemented for processing biotherapeutics, others are still at an early stage of feasibility assessment. An overview of each method is presented, detailing the comparison to lyophilization, examining the advantages and disadvantages of each technology, and evaluating the potential of each to be utilized for drying biotherapeutic products.

Quality control: Is there quality control of localized mRNAs?

In eukaryotic cells many mRNAs are localized to specific regions of the cytosol, thereby allowing the local production of proteins. The process of mRNA localization can be coordinated with mRNA turnover, which can also be spatially controlled to increase the degree of mRNA localization. The coordination of mRNA localization, translation repression during transport, and mRNA degradation suggests the hypothesis that an additional layer of mRNA quality control exists in cells to degrade mRNAs that fail to be appropriately localized.

Edc3 function in yeast and mammals is modulated by interaction with NAD-related compounds.

The control of mRNA translation and degradation is mediated in part by a set of proteins that can inhibit translation and promote decapping, as well as function in the assembly of cytoplasmic mRNP granules referred to as processing bodies (P-bodies). The conserved enhancer of mRNA decapping 3 (Edc3) protein functions to promote both decapping and P-body assembly. Crystal structures of the YjeF_N domain in hEdc3 identified a putative binding site for a small molecule. Structure modeling of the human Edc3 Yjef_N along with other Yjef_N-containing proteins suggests that this molecule is related to NAD(H). We now show human Edc3 directly binds NADH. We also show that human and yeast Edc3 chemically modify NAD in vitro. Mutations that are predicted to disrupt the binding and/or hydrolysis of an NAD-related molecule by yeast and human Edc3 affect the control of mRNA degradation and/or P-body composition in vivo. This suggests that the interaction of Edc3 with an NAD-related molecule affects its function in the regulation of mRNA translation and degradation and provides a possible mechanism to couple the energetics of the cell to posttranscriptional control. Moreover, this provides a unique example of and lends strength to the postulated connection of metabolites, enzymes, and RNA.

Modeling and analysis of high-performance, multicolored anti-reflection coatings for solar cells.

In this work solar cell anti-reflection coatings tuned to give a specific hue under solar illumination are investigated. We demonstrate that it is possible to form patterned coatings with large color contrast and high transmittance. We use colorimetric and thin film optics models to explore the relationship between the color and performance of bilayer anti-reflection coatings on Si, and predict the photocurrent generation from an example Si solar cell. The colorimetric predictions were verified by measuring a series of coatings deposited on Si substrates. Finally, a patterned Si sample was produced using a simple, low-cost photolithography procedure to selectively etch only the top layer of a bilayer coating to demonstrate a high-performance anti-reflection coating with strong color contrast.

Elongation kinetics of polyglutamine peptide fibrils: a quartz crystal microbalance with dissipation study.

Abnormally expanded polyglutamine domains in proteins are associated with several neurodegenerative diseases, including Huntington's disease. Expansion of the polyglutamine (polyQ) domain facilitates aggregation of the affected protein, and several studies directly link aggregation to neurotoxicity. Studies of synthetic polyQ peptides have contributed substantially to our understanding of the mechanism of aggregation. In this report, polyQ fibrils were immobilized onto a sensor, and their elongation by polyQ peptides of various length and conformation was examined using quartz crystal microbalance with dissipation monitoring (QCM-D). The rate of elongation increased as the peptide length increased from 8 to 24 glutamines (Q8, Q20, and Q24). Monomer conformation affected elongation rates: insertion of a ß-turn template d-Pro-Gly in the center of the peptide increased elongation rates several-fold, while insertion of Pro-Pro dramatically slowed elongation. Dissipation measurements of the QCM-D provided qualitative information about mechanical properties of the elongating fibrils. These data showed clear differences in the characteristics of the elongating aggregates, depending on the specific identity of the associating polyQ peptide. Elongation rates were sensitive to the pH and ionic strength of the buffer. Comparison of QCM-D data with those obtained by optical waveguide lightmode spectroscopy revealed that very little water was associated with the elongation of fibrils by the peptide containing d-Pro-Gly, but a significant amount of water was associated when the fibrils were elongated by Q20. Together, the data indicate that elongation of polyQ fibrils can occur without full consolidation to the fibril structure, resulting in variations to the aggregate structure during elongation.

Attenuation of neurovirulence, biodistribution, and shedding of a poliovirus:rhinovirus chimera after intrathalamic inoculation in Macaca fascicularis.

A dependence of poliovirus on an unorthodox translation initiation mode can be targeted selectively to drive viral protein synthesis and cytotoxicity in malignant cells. Transformed cells are naturally susceptible to poliovirus, due to widespread ectopic upregulation of the poliovirus receptor, Necl-5, in ectodermal/neuroectodermal cancers. Viral tumor cell killing and the host immunologic response it engenders produce potent, lasting antineoplastic effects in animal tumor models. Clinical application of this principle depends on unequivocal demonstration of safety in primate models for paralytic poliomyelitis. We conducted extensive dose-range-finding, toxicity, biodistribution, shedding, and neutralizing antibody studies of the prototype oncolytic poliovirus recombinant, PVS-RIPO, after intrathalamic inoculation in Macaca fascicularis. These studies suggest that intracerebral PVS-RIPO inoculation does not lead to viral propagation in the central nervous system (CNS), does not cause histopathological CNS lesions or neurological symptoms that can be attributed to the virus, is not associated with extraneural virus dissemination or replication and does not induce shedding of virus with stool. Intrathalamic PVS-RIPO inoculation induced neutralizing antibody responses against poliovirus serotype 1 in all animals studied.