Corrigendum: Comparative microbiome analysis of beef cattle, the feedyard environment, and airborne particulate matter as a function of probiotic and antibiotic use, and change in pen environment.

[This corrects the article DOI: 10.3389/fmicb.2024.1348171.].

Oil and gas platforms degrade benthic invertebrate diversity and food web structure.

Oil and gas exploitation introduces toxic contaminants such as hydrocarbons and heavy metals to the surrounding sediment, resulting in deleterious impacts on marine benthic communities. This study combines benthic monitoring data over a 30-year period in the North Sea with dietary information on >1400 taxa to quantify the effects of active oil and gas platforms on benthic food webs using a multiple before-after control-impact experiment. Contamination from oil and gas platforms caused declines in benthic food web complexity, community abundance, and biodiversity. Fewer trophic interactions and increased connectance indicated that the community became dominated by generalists adapting to alternative resources, leading to simpler but more connected food webs in contaminated environments. Decreased mean body mass, shorter food chains, and the dominance of small detritivores such as Capitella capitata near to structures suggested a disproportionate loss of larger organisms from higher trophic levels. These patterns were associated with concentrations of hydrocarbons and heavy metals that exceed OSPAR's guideline thresholds of sediment toxicity. This study provides new evidence to better quantify and manage the environmental consequences of oil and gas exploitation at sea.

Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria.

Inhibition of the biosynthesis of bacterial heptoses opens novel perspectives for antimicrobial therapies. The enzyme GmhA responsible for the first committed biosynthetic step catalyzes the conversion of sedoheptulose 7-phosphate into d-glycero-d-manno-heptose 7-phosphate and harbors a Zn2+ ion in the active site. A series of phosphoryl- and phosphonyl-substituted derivatives featuring a hydroxamate moiety were designed and prepared from suitably protected ribose or hexose derivatives. High-resolution crystal structures of GmhA complexed to two N-formyl hydroxamate inhibitors confirmed the binding interactions to a central Zn2+ ion coordination site. Some of these compounds were found to be nanomolar inhibitors of GmhA. While devoid of HepG2 cytotoxicity and antibacterial activity of their own, they demonstrated in vitro lipopolysaccharide heptosylation inhibition in Enterobacteriaceae as well as the potentiation of erythromycin and rifampicin in a wild-type Escherichia coli strain. These inhibitors pave the way for a novel treatment of Gram-negative infections.

Comparative microbiome analysis of beef cattle, the feedyard environment, and airborne particulate matter as a function of probiotic and antibiotic use, and change in pen environment.

Introduction: Intensive beef cattle production systems are frequently implicated as a source of bacteria that can be transferred to nearby humans and animals via effluent water, manure used as fertilizer, or airborne particulate matter. It is crucial to understand microbial population dynamics due to manure pack desiccation, antibiotic usage, and antibiotic alternatives within beef cattle and their associated feedyard environment. Understanding how bacterial communities change in the presence of antibiotics can also improve management practices for reducing the spread of foodborne bacteria. Methods: In this study, we aimed to compare the microbiomes within cattle feces, the feedyard environment and artificially produced airborne particulate matter as a function of pen change and treatment with tylosin or probiotics. We utilized 16S rRNA sequencing to compare bacterial communities among sample types, study days, and treatment groups. Results: Bacterial community diversity varied as a function of sampling day and pen change (old or new) within fecal and manure pack samples. Manure pack samples from old pens and new pens contained diverse communities of bacteria on days 0 and 84; however, by day 119 of the study these taxonomic differences were less evident. Particulate matter samples exhibited significant differences in community diversity and predominant bacterial taxa compared to the manure pack they originated from. Treatment with tylosin did not meaningfully impact bacterial communities among fecal, environmental, or particulate matter samples; however, minor differences in bacterial community structure were observed in feces from cattle treated with probiotics. Discussion: This study was the first to characterize and compare microbial communities within feces, manure pack, and airborne particulate matter from the same location and as a function of tylosin and probiotic treatment, and pen change. Although fecal and environmental samples are commonly used in research studies and other monitoring programs to infer public health risk of bacteria and antimicrobial resistance determinants from feedyard environments, our study suggests that these samples may not be appropriate to infer public health risk associated with airborne particulate matter.

Climate change affects the distribution of diversity across marine food webs.

Many studies predict shifts in species distributions and community size composition in response to climate change, yet few have demonstrated how these changes will be distributed across marine food webs. We use Bayesian Additive Regression Trees to model how climate change will affect the habitat suitability of marine fish species across a range of body sizes and belonging to different feeding guilds, each with different habitat and feeding requirements in the northeast Atlantic shelf seas. Contrasting effects of climate change are predicted for feeding guilds, with spatially extensive decreases in the species richness of consumers lower in the food web (planktivores) but increases for those higher up (piscivores). Changing spatial patterns in predator-prey mass ratios and fish species size composition are also predicted for feeding guilds and across the fish assemblage. In combination, these changes could influence nutrient uptake and transformation, transfer efficiency and food web stability, and thus profoundly alter ecosystem structure and functioning.

Pregnancy and breastfeeding in mental health policy: a narrative review.

OBJECTIVES: Mental health difficulties are often exacerbated during the perinatal period. Policy and guidelines are increasingly being used to enhance the quality of healthcare. We conducted a literature review of published research relating to pregnancy and breastfeeding in mental health policy. METHODS: Relevant terms were searched in Medline, CINAHL, APA PsycINFO and EMBASE for articles published in English from 1970 until 2020. Only papers that referenced policy, guidance, legislation or standards were included. While a systematic approach was used, the nature of the results necessitated a narrative review. RESULTS: Initially, 262 papers were identified, 44 met the inclusion criteria. Reproductive health is given sparse consideration in research relating to mental health policy. Despite this, some key areas emerged. These included: the need for proactive preconception psychoeducation, proactive screening of mothers of infants and young children for perinatal mental health issues, enhanced prescribing practice for women of child-bearing age, enhanced monitoring during pregnancy, development of safe modification of coercive practices should they need to be employed in emergency circumstances and targeted measures to reduce substance misuse. Themes that arose relating to breastfeeding and bonding are also described. CONCLUSIONS: Female reproductive health is often ignored in research relating to mental health policy, guidelines and standards. These tools need to be harnessed to promote good healthcare. Reproductive health should be included in the care plan of all mental health patients. These topics need to be integrated into existing relevant policies and not isolated to a separate policy.

Human Performance in Competitive and Collaborative Human-Machine Teams.

In the modern world, many important tasks have become too complex for a single unaided individual to manage. Teams conduct some safety-critical tasks to improve task performance and minimize the risk of error. These teams have traditionally consisted of human operators, yet, nowadays, artificial intelligence and machine systems are incorporated into team environments to improve performance and capacity. We used a computerized task modeled after a classic arcade game to investigate the performance of human-machine and human-human teams. We manipulated the group conditions between team members; sometimes, they were instructed to collaborate, compete, or work separately. We evaluated players' performance in the main task (gameplay) and, in post hoc analyses, participant behavioral patterns to inform group strategies. We compared game performance between team types (human-human vs. human-machine) and group conditions (competitive, collaborative, independent). Adapting workload capacity analysis to human-machine teams, we found performance under both team types and all group conditions suffered a performance efficiency cost. However, we observed a reduced cost in collaborative over competitive teams within human-human pairings, but this effect was diminished when playing with a machine partner. The implications of workload capacity analysis as a powerful tool for human-machine team performance measurement are discussed.

Ostreopsis Schmidt and Coolia Meunier (Dinophyceae, Gonyaulacales) from Cook Islands and Niue (South Pacific Ocean), including description of Ostreopsis tairoto sp. nov.

It is important to decipher the diversity and distribution of benthic dinoflagellates, as there are many morphologically indistinct taxa that differ from one another in production of potent toxins. To date, the genus Ostreopsis comprises twelve described species, of which seven are potentially toxic and produce compounds presenting a threat to human and environmental health. In this study, isolates previously identified as "Ostreopsis sp. 3" were sampled from the area where it was first reported, Rarotonga, Cook Islands, and have been taxonomically and phylogenetically characterised as Ostreopsis tairoto sp. nov. Phylogenetically, the species is closely related to "Ostreopsis sp. 8", O. mascarenensis, "O. sp. 4", O. fattorussoi, O. rhodesiae and O. cf. siamensis. Previously, it was considered a part of the O. cf. ovata complex but can be distinguished from O. cf. ovata based on the small pores identified on this study, and from O. fattorussoi and O. rhodesiae based on relative lengths of the 2' plates. No known palytoxin -like compounds were detected in strains investigated in this study. Strains of O. lenticularis, Coolia malayensis and C. tropicalis were also identified and described. This study advances our knowledge of biogeography, distribution, and toxins of Ostreopsis and Coolia species.

Role of Half-of-Sites Reactivity and Inter-Subunit Communications in DAHP Synthase Catalysis and Regulation.

α-Carboxyketose synthases, including 3-deoxy-d-arabinoheptulosonate 7-phosphate synthase (DAHPS), are long-standing targets for inhibition. They are challenging targets to create tight-binding inhibitors against, and inhibitors often display half-of-sites binding and partial inhibition. Half-of-sites inhibition demonstrates the existence of inter-subunit communication in DAHPS. We used X-ray crystallography and spatially resolved hydrogen-deuterium exchange (HDX) to reveal the structural and dynamic bases for inter-subunit communication in Escherichia coli DAHPS(Phe), the isozyme that is feedback-inhibited by phenylalanine. Crystal structures of this homotetrameric (dimer-of-dimers) enzyme are invariant over 91% of its sequence. Three variable loops make up 8% of the sequence and are all involved in inter-subunit contacts across the tight-dimer interface. The structures have pseudo-twofold symmetry indicative of inter-subunit communication across the loose-dimer interface, with the diagonal subunits B and C always having the same conformation as each other, while subunits A and D are variable. Spatially resolved HDX reveals contrasting responses to ligand binding, which, in turn, affect binding of the second substrate, erythrose-4-phosphate (E4P). The N-terminal peptide, M1-E12, and the active site loop that binds E4P, F95-K105, are key parts of the communication network. Inter-subunit communication appears to have a catalytic role in all α-carboxyketose synthase families and a regulatory role in some members.

Practising pharmacists want more nutrition education.

BACKGROUND AND PURPOSE: Although pharmacists are first and foremost medication specialists and suppliers, in Australia they are also ideally positioned within the healthcare setting to encourage and support positive lifestyle choices in the community. Little has been done to assess their nutrition knowledge in over 20 years. We aimed to explore pharmacists' nutrition knowledge and associated practice and to subsequently develop and evaluate a short course to fill identified gaps. EDUCATIONAL ACTIVITY AND SETTING: The General Nutrition Knowledge Questionnaire was revised for testing nutrition knowledge in the pharmacy setting. Once validated, the questionnaire was distributed to pharmacists using social/professional media advertising. A short course was then developed, and its effectiveness assessed on final-year pharmacy students. FINDINGS: Pharmacists' (N = 258) mean score was 89.9 out of 121 (SD = 10.6) with significant variation. Nutrition education provision in practice was provided inconsistently and was associated with how strongly participants rated their own knowledge. Most pharmacists (95.7%) agreed they are well-placed to assist in disease burden reduction through nutrition education; however, most (98.4%) felt their knowledge needed improvement. The short course was well received by participants, deemed to be appropriate in context, and resulted in a median improvement in matched scores of 14.7% (P < .001) with no significant decline in knowledge when reassessed three weeks later (P = .383). SUMMARY: Pharmacists' nutrition knowledge and practice was variable. Further education can improve knowledge without significant time outlay and is likely to improve associated counselling practices.

Exploring the Impact of the "RUEU?" Game on Greek Students' Perceptions of and Attitudes to European Identity.

European identity is a complex, multi-faced and inherently imprecise concept relating to a range of socio-political and psychological factors. Addressing this topic in educational practice, particularly with respect to Higher Education students, constitutes a complex and open problem for research. This paper reports on an experimental study designed to explore the effectiveness of the educational game "RUEU?" in supporting university students in understanding the key socio-political issues regarding European identity. Quantitative data regarding Greek university students' (N = 92) attitudes to European identity, before and after playing the game, were collected. Students' performance of the game group (N = 46) was compared with that of a control group (N = 46) who explored the same issues about European identity through a tutor-guided discussion. The findings showed that both instructional interventions were effective but in different ways. The participants in the game-based group appeared more attached to the EU after the intervention and moved toward a more balanced description of their Greek and European identity. On the other hand, the students in the control group rated higher what "European identity" and being EU citizen means to them. The findings indicated the potential of game-based interventions to deliver not only academic content but also to promote students' reflection and influence them at an attitudinal and emotional level.

Natural history of retinal degeneration in ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinoses.

Neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of inherited neurodegenerative diseases with a common set of symptoms including cognitive and motor decline and vision loss. Naturally occurring sheep models of CLN5 and CLN6 disease display the key clinical features of NCL, including a progressive loss of vision. We assessed retinal histology, astrogliosis, and lysosomal storage accumulation in CLN5 affected (CLN5-/-) and CLN6 affected (CLN6-/-) sheep eyes and age-matched controls at 3, 6, 12, and 18 months of age to determine the onset and progression of retinal pathology in NCL sheep. The retina of CLN5-/- sheep shows progressive atrophy of the outer retinal layers, widespread gliosis, and accumulation of lysosomal storage in retinal ganglion cells late in disease. In contrast, CLN6-/- retina shows significant atrophy of all retinal layers, progressive gliosis, and earlier accumulation of lysosomal storage. This study has highlighted the differential vulnerability of retinal layers and the time course of retinal atrophy in two distinct models of NCL disease. This data will be valuable in determining potential targets for ocular therapies and the optimal timing of these therapies for protection from retinal dysfunction and degeneration in NCL.

Lanthanoid Biphenolates as a Rich Source of Lanthanoid-Main Group Heterobimetallic Complexes.

Several new trivalent dinuclear rare earth 2,2'-methylenebis(6-tert-butyl-4-methylphenolate) (mbmp2- ) complexes with the general form [Ln2 (mbmp)3 (thf)n ] (Ln=Sm 1, Tb 2 (n=3), and Ho 3, Yb 4 (n=2), and a tetravalent cerium complex [Ce(mbmp)2 (thf)2 ] (5) have been synthesised by RTP (redox transmetallation/protolysis) reactions from lanthanoid metals, Hg(C6 F5 )2 and the biphenol mbmpH2 . These new complexes and some previously reported partially protonated rare earth biphenolate complexes [Ln(mbmp)(mbmpH)(thf)n ] react with lithium, aluminium, potassium and zinc organometallic reagents to form lanthanoid-main group heterobimetallic species. When reaction mixtures containing the Ln biphenolate complexes were treated with n-butyllithium, both molecular ([Li(thf)2 Ln(mbmp)2 (thf)n ] (Ln=La 6, Pr 7 (n=2) and Er 8, Yb 9, and Lu 10 (n=1)) and charge separated ([Li(thf)4 ][Ln(mbmp)2 (thf)2 ] (Ln=Y 11, Sm 12, Dy 13, and Ho 14) complexes were isolated. Treatment with trimethylaluminium also led to isolation of molecular ([AlMe2 Ln(mbmp)2 (thf)2 ] (Ln=Pr 15, Sm 16, and Tb 17)) and ionic [La(mbmp)(thf)5 ][AlMe2 (mbmp)] (18) complexes. One gadolinium-potassium ([K(thf)3 Gd(mbmp)2 (thf)2 ] (19)), and one ytterbium-zinc species ([ZnEtYb(mbmp)2 (thf)] (20)) were isolated from treatment of reaction mixtures with potassium bis(trimethylsilyl)amide and diethylzinc respectively.

Assessment of Patient Satisfaction Among Cancer Patients Undergoing Radiotherapy.

The patient-provider relationship is a key driver of patient satisfaction as it relates to overall healthcare experience. We surveyed patients undergoing radiation therapy to determine what they consider to be the most valued qualities in their interactions with the healthcare team. An ethics-approved 35-item patient satisfaction survey was developed in-house to gain insights on patients' perception of their relationship with the healthcare team throughout their cancer journey. There were 199 completed survey, median age 68 years, 54% women and 45% men. Almost all (95%) "agreed" or "strongly agreed" that their physicians had been sensitive and compassionate. Over 90% felt that they received adequate explanations about their treatment, and had their questions answered. The vast majority (93%) felt included in the decision-making process. Patients reported the 5 most highly rated qualities among their healthcare providers (HCPs) as knowledge, kindness, honesty, good communication, and a cheerful attitude. Overall satisfaction was high but areas for improvement were identified including being offered future appointments for further discussion, more information about clinical trials, other treatments, and community resources. Patients noted their HCPs tended to focus on the physical and emotional needs of patients, but spiritual and cultural needs were rarely addressed. Patients receiving radiotherapy reported high rates of satisfaction across many aspects of their care. These findings also reinforce the different aspects of holistic care that can be improved, and serve as a reminder to clinicians that patients perceive their role as more than just that of a medical expert.

An Inhibitor-in-Pieces Approach to DAHP Synthase Inhibition: Potent Enzyme and Bacterial Growth Inhibition.

3-Deoxy-d-arabinoheptulosonate-7-phosphate (DAHP) synthase catalyzes the first step in the shikimate biosynthetic pathway and is an antimicrobial target. We used an inhibitor-in-pieces approach, based on the previously reported inhibitor DAHP oxime, to screen inhibitor fragments in the presence and absence of glycerol 3-phosphate to occupy the distal end of the active site. This led to DAHP hydrazone, the most potent inhibitor to date, Ki = 10 ± 1 nM. Three trifluoropyruvate (TFP)-based inhibitor fragments were efficient inhibitors with ligand efficiencies of up to 0.7 kcal mol-1/atom compared with 0.2 kcal mol-1/atom for a typical good inhibitor. The crystal structures showed the TFP-based inhibitors binding upside down in the active site relative to DAHP oxime, providing new avenues for inhibitor development. The ethyl esters of TFP oxime and TFP semicarbazone prevented E. coli growth in culture with IC50 = 0.21 ± 0.01 and 0.77 ± 0.08 mg mL-1, respectively. Overexpressing DAHP synthase relieved growth inhibition, demonstrating that DAHP synthase was the target. Growth inhibition occurred in media containing aromatic amino acids, suggesting that growth inhibition was due to depletion of some other product(s) of the shikimate pathway, possibly folate.

New lanthanoid biphenolate complexes, their further reactivity with trimethylaluminium and catalytic activity for the polymerisation of rac-lactide.

A series of rare earth biphenolate complexes of the general form [Ln(mbmp)(mbmpH)(thf)3] (Ln = Y (1), Nd (2), Gd (3), Dy (4), Er (5), Tm (6) and Lu (7)) have been synthesised by redox transmetallation/protolysis (RTP) from the free rare earth metal, Hg(C6F5)2 and 2,2'-methylenebis(6-tert-butyl-4-methylphenol) (mbmpH2). The rare earth metal is six coordinate with one chelating biphenolate mbmp2- ligand and one unidentate monophenolate mbmpH- ligand. The yttrium complex, when crystallised from hot toluene or deuterated benzene, loses a coordinated thf and exhibits coordination through all three phenolate oxygen atoms, as well as the oxygen of the phenol, yielding two solvates [Y(mbmp)(mbmpH)(thf)2]·nsolv (solv = PhMe, n = 1 (8a) or C6D6, n = 2 (8b)). Of these rare earth complexes, the yttrium derivative (1) yielded the heterobimetallic complex [AlMe2Y(mbmp)2(thf)2] (9) when treated with trimethylaluminium, whereas all other complexes produced the transmetallation product [AlMe(mbmp)(thf)] (11). The dinuclear dysprosium complex [Dy2(mbmp)3(thf)3] (10) was isolated alongside 11 from the reaction of 4 with trimethylaluminium, suggesting trimethylaluminium instigates a redistribution reaction. The ROP activity of the mononuclear neodymium, dysprosium, lutetium, and aluminium complexes towards rac-lactide in toluene at 70 °C was found to be poor compared to rare earth complexes of monodentate aryloxides, but increased with increased rare earth ion size.

InterCarb: A Community Effort to Improve Interlaboratory Standardization of the Carbonate Clumped Isotope Thermometer Using Carbonate Standards.

Increased use and improved methodology of carbonate clumped isotope thermometry has greatly enhanced our ability to interrogate a suite of Earth-system processes. However, interlaboratory discrepancies in quantifying carbonate clumped isotope (Δ47) measurements persist, and their specific sources remain unclear. To address interlaboratory differences, we first provide consensus values from the clumped isotope community for four carbonate standards relative to heated and equilibrated gases with 1,819 individual analyses from 10 laboratories. Then we analyzed the four carbonate standards along with three additional standards, spanning a broad range of δ47 and Δ47 values, for a total of 5,329 analyses on 25 individual mass spectrometers from 22 different laboratories. Treating three of the materials as known standards and the other four as unknowns, we find that the use of carbonate reference materials is a robust method for standardization that yields interlaboratory discrepancies entirely consistent with intralaboratory analytical uncertainties. Carbonate reference materials, along with measurement and data processing practices described herein, provide the carbonate clumped isotope community with a robust approach to achieve interlaboratory agreement as we continue to use and improve this powerful geochemical tool. We propose that carbonate clumped isotope data normalized to the carbonate reference materials described in this publication should be reported as Δ47 (I-CDES) values for Intercarb-Carbon Dioxide Equilibrium Scale.

Systematic variation in food web body-size structure linked to external subsidies.

The relationship between body mass (M) and size class abundance (N) depicts patterns of community structure and energy flow through food webs. While the general assumption is that M and N scale linearly (on log-log axes), nonlinearity is regularly observed in natural systems, and is theorized to be driven by nonlinear scaling of trophic level (TL) with M resulting in the rapid transfer of energy to consumers in certain size classes. We tested this hypothesis with data from 31 stream food webs. We predicted that allochthonous subsidies higher in the web results in nonlinear M-TL relationships and systematic abundance peaks in macroinvertebrate and fish size classes (latter containing salmonids), that exploit terrestrial plant material and terrestrial invertebrates, respectively. Indeed, both M-N and M-TL significantly deviated from linear relationships and the observed curvature in M-TL scaling was inversely related to that observed in M-N relationships. Systemic peaks in M-N, and troughs in M-TL occurred in size classes dominated by generalist invertebrates, and brown trout. Our study reveals how allochthonous resources entering high in the web systematically shape community size structure and demonstrates the relevance of a generalized metabolic scaling model for understanding patterns of energy transfer in energetically 'open' food webs.

Single-arm, open label prospective trial to assess prediction of the role of ERCC1/XPF complex in the response of advanced NSCLC patients to platinum-based chemotherapy.

BACKGROUND: Platinum-based therapy, combined or not with immune checkpoint inhibitors, represents a front-line choice for patients with non-small-cell lung cancer (NSCLC). Despite the improved outcomes in the last years for this malignancy, only a sub-group of patients have long-term benefit. Excision repair cross-complementation group 1 (ERCC1) has been considered a potential biomarker to predict the outcome of platinum-based chemotherapy in NSCLC. However, the ERCC1 gene is transcribed in four splice variants where the isoform 202 was described as the only one active and able to complex Xeroderma pigmentosum group F-complementing protein (XPF). Here, we prospectively investigated if the active form of ERCC1, as assessed by the ERCC1/XPF complex (ERCC1/XPF), could predict the sensitivity to platinum compounds. PATIENTS AND METHODS: Prospectively enrolled, patients with advanced NSCLC treated with a first-line regimen containing platinum were centrally evaluated for ERCC1/XPF by a proximity ligation assay. Overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) were analyzed. RESULTS: The absence of the ERCC1/XPF in the tumor suggested a trend of worst outcomes in terms of both OS [hazard ratio (HR) 1.41, 95% confidence interval (CI) 0.67-2.94, P = 0.373] and PFS (HR 1.61, 95% CI 0.88-3.03, P = 0.123). ORR was marginally influenced in ERCC1/XPF-negative and -positive groups [odds ratio (stable disease + progressive disease versus complete response + partial response) 0.87, 95% CI 0.25-3.07, P = 0.832]. CONCLUSION: The lack of ERCC1/XPF complex in NSCLC tumor cells might delineate a group of patients with poor outcomes when treated with platinum compounds. ERCC1/XPF absence might well identify patients for whom a different therapeutic approach could be necessary.

Utilization of redox modulating small molecules that selectively act as pro-oxidants in cancer cells to open a therapeutic window for improving cancer therapy.

There is a rapidly growing body of literature supporting the notion that differential oxidative metabolism in cancer versus normal cells represents a metabolic frailty that can be exploited to open a therapeutic window into cancer therapy. These cancer cell-specific metabolic frailties may be amenable to manipulation with non-toxic small molecule redox active compounds traditionally thought to be antioxidants. In this review we describe the potential mechanisms and clinical applicability in cancer therapy of four small molecule redox active agents: melatonin, vitamin E, selenium, and vitamin C. Each has shown the potential to have pro-oxidant effects in cancer cells while retaining antioxidant activity in normal cells. This dichotomy can be exploited to improve responses to radiation and chemotherapy by opening a therapeutic window based on a testable biochemical rationale amenable to confirmation with biomarker studies during clinical trials. Thus, the unique pro-oxidant/antioxidant properties of melatonin, vitamin E, selenium, and vitamin C have the potential to act as effective adjuvants to traditional cancer therapies, thereby improving cancer patient outcomes.