Melatonin Supplementation for Cancer-Related Fatigue in Patients With Early Stage Breast Cancer Receiving Radiotherapy: A Double-Blind Placebo-Controlled Trial.

BACKGROUND: Fatigue is common in patients undergoing radiotherapy (RT) and can significantly impact quality of life. Melatonin, a safe inexpensive natural supplement, may improve symptoms and attenuate the side effects of RT. The purpose of this randomized double-blind placebo-controlled phase III trial was to assess the effects of melatonin for preventing fatigue and other symptoms in patients with breast cancer undergoing RT. METHODS: Female early stage or Ductal carcinoma in situ patients with breast cancer ≥18 years of age with Eastern Cooperative Oncology Group (ECOG) performance status <3, hemoglobin ≥9 g/dL, planned for outpatient RT treatment with curative intent, were randomized 1:1 to melatonin 20 mg or placebo, orally, starting the night before RT initiation until 2 weeks post-RT. Randomization was stratified according to treatment duration (<3 weeks, ≥3 weeks) and prior chemotherapy. The primary endpoint was the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue scale), and secondary endpoints were FACIT-F subscales, Edmonton Symptom Assessment Scale (ESAS), and Patient-Reported Outcomes Measurement Information System (PROMIS) scores obtained at baseline, and 2 and 8 weeks post-RT. A 2-sided ANOVA F-test at a 4.5% significance level for the primary endpoint was used. Secondary analyses were reported using an F-test at a 5% significance level. The goal was to recruit approximately 140 patients with interim analysis planned mid-recruitment. RESULTS: Eighty-five patients were screened for eligibility; 79 patients were randomized: 40 to melatonin and 39 to placebo; 78 patients were treated and included in the interim analysis at the mid-recruitment point. Baseline patient characteristics of age, race, and ECOG performance status were similar in both arms. The treatment effect was studied using a longitudinal mixed effects model with the effect of treatment over time (treatment × time) as the primary outcome parameter. The treatment × time for FACIT-Fatigue did not demonstrate statistical significance (P-value .83) in the melatonin group compared to placebo. In addition, secondary analyses of FACIT physical, social, emotional, and functional well-being scores did not demonstrate statistical significance (P-values of .35, .06, .62, and .71, respectively). Total PROMIS scores, collected as secondary outcome reported by patients, did not demonstrate statistically significant change over time either (P-value is .34). The other secondary scale, ESAS, was analyzed for each individual item and found to be nonsignificant, anxiety (P = .56), well-being (.82), drowsiness (.83), lack of appetite (.35), nausea (.79), pain (.50), shortness of breath (.77), sleep (.45), and tiredness (.56). Depression was the only item demonstrating statistical significance with a decrease of 0.01 unit in the placebo group, a change not considered clinically significant. Melatonin was well-tolerated with no grade 3 or 4 adverse events reported. The most common side effects were headache, somnolence, and abdominal pain. No patients died while participating in this study. Two patients died within a year of study completion from breast cancer recurrence. Sixteen patients withdrew prior to study completion for various reasons including adverse events, hospitalizations unrelated to study drug, RT discontinuation, and COVID-19 precautions. CONCLUSIONS: In this double-blind placebo-controlled phase III trial, melatonin did not prevent or significantly improve fatigue and other symptoms in patients with early stage breast cancer undergoing RT. The analysis, showing little evidence of an effect, at mid-recruitment, assured early termination of the trial.

An in situ transmission electron microscopy study of sintering and redispersion phenomena over size-selected metal nanoparticles: environmental effects.

The thermal and chemical stability of micelle-synthesized size-selected Pt nanoparticles (NPs) supported on thin SiO2 (20 nm) films was monitored in situ via transmission electron microscopy (TEM) under pure hydrogen and pure oxygen environments. The coarsening treatment was performed for 30 min at each temperature (1 Torr of either O2 or H2), while the TEM measurements were carried out at 1 Torr of H2 and 0.5 Torr of O2. Surprisingly, the NPs were found to be stable against sintering under both gaseous atmospheres up to 650 °C. Nevertheless, drastic sintering via diffusion-coalescence was observed upon annealing in H2 at 800 °C. In contrast, an identically prepared sample demonstrated lack of agglomeration at the same temperature under O2. The latter observation is ascribed to a strengthened chemical bond at the NP/support interface due to the formation of PtOx species at low temperature. Subsequently, oxidative NP redispersion - associated with some loss of Pt due to the formation of volatile PtOx species - is inferred from the behavior in O2 at/above 650 °C. In contrast, SiO2 reduction catalyzed by the presence of the Pt NPs and Pt silicide formation was found in H2 at 800 °C, which might play a role in the enhanced coarsening observed. Subsequent exposure of the PtSi NPs to oxygen led to the formation of Pt-SiO2 core-shell structures. Our findings highlight the dynamic structural transformations that nanoscale materials experience under different environments and the important role played by their initial size, size distribution and dispersion on their stability against sintering.

Updates in Cancer Cachexia: Clinical Management and Pharmacologic Interventions.

Despite a better understanding of the mechanisms causing cancer cachexia (CC) and development of promising pharmacologic and supportive care interventions, CC persists as an underdiagnosed and undertreated condition. CC contributes to fatigue, poor quality of life, functional impairment, increases treatment related toxicity, and reduces survival. The core elements of CC such as weight loss and poor appetite should be identified early. Currently, addressing contributing conditions (hypothyroidism, hypogonadism, and adrenal insufficiency), managing nutrition impact symptoms leading to decreased oral intake (nausea, constipation, dysgeusia, stomatitis, mucositis, pain, fatigue, depressed mood, or anxiety), and the addition of pharmacologic agents when appropriate (progesterone analog, corticosteroids, and olanzapine) is recommended. In Japan, the clinical practice has changed based on the availability of Anamorelin, a ghrelin receptor agonist that improved lean body mass, weight, and appetite-related quality of life (QoL) compared to a placebo, in phase III trials. Other promising therapeutic agents currently in trials include Espindolol, a non-selective ß blocker and a monoclonal antibody to GDF-15. In the future, a single therapeutic agent or perhaps multiple medications targeting the various mechanisms of CC may prove to be an effective strategy. Ideally, these medications should be incorporated into a multimodal interdisciplinary approach that includes exercise and nutrition.

Aphid gene expression following polerovirus acquisition is host species dependent.

Upon acquisition of persistent circulative viruses such as poleroviruses, the virus particles transcytose through membrane barriers of aphids at the midgut and salivary glands via hemolymph. Such intricate interactions can influence aphid behavior and fitness and induce associated gene expression in viruliferous aphids. Differential gene expression can be evaluated by omics approaches such as transcriptomics. Previously conducted aphid transcriptome studies used only one host species as the source of virus inoculum. Viruses typically have alternate hosts. Hence, it is not clear how alternate hosts infected with the same virus isolate alter gene expression in viruliferous vectors. To address the question, this study conducted a transcriptome analysis of viruliferous aphids that acquired the virus from different host species. A polerovirus, cotton leafroll dwarf virus (CLRDV), which induced gene expression in the cotton aphid, Aphis gossypii Glover, was assessed using four alternate hosts, viz., cotton, hibiscus, okra, and prickly sida. Among a total of 2,942 differentially expressed genes (DEGs), 750, 310, 1,193, and 689 genes were identified in A. gossypii that acquired CLRDV from infected cotton, hibiscus, okra, and prickly sida, respectively, compared with non-viruliferous aphids that developed on non-infected hosts. A higher proportion of aphid genes were overexpressed than underexpressed following CLRDV acquisition from cotton, hibiscus, and prickly sida. In contrast, more aphid genes were underexpressed than overexpressed following CLRDV acquisition from okra plants. Only four common DEGs (heat shock protein, juvenile hormone acid O-methyltransferase, and two unannotated genes) were identified among viruliferous aphids from four alternate hosts. Gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations indicated that the acquisition of CLRDV induced DEGs in aphids associated with virus infection, signal transduction, immune systems, and fitness. However, these induced changes were not consistent across four alternate hosts. These data indicate that alternate hosts could differentially influence gene expression in aphids and presumably aphid behavior and fitness despite being infected with the same virus isolate.

Evaluation of Wild Peanut Species and Their Allotetraploids for Resistance against Thrips and Thrips-Transmitted Tomato Spotted Wilt Orthotospovirus (TSWV).

Thrips-transmitted tomato spotted wilt orthotospovirus (TSWV) causes spotted wilt disease in peanut (Arachis hypogaea L.) and limits yield. Breeding programs have been developing TSWV-resistant cultivars, but availability of sources of resistance against TSWV in cultivated germplasm is extremely limited. Diploid wild Arachis species can serve as important sources of resistance, and despite ploidy barriers (cultivated peanut is tetraploid), their usage in breeding programs is now possible because of the knowledge and development of induced interspecific allotetraploid hybrids. This study screened 10 wild diploid Arachis and six induced allotetraploid genotypes via thrips-mediated TSWV transmission assays and thrips' feeding assays in the greenhouse. Three parameters were evaluated: percent TSWV infection, virus accumulation, and temporal severity of thrips feeding injury. Results indicated that the diploid A. stenosperma accession V10309 and its derivative-induced allotetraploid ValSten1 had the lowest TSWV infection incidences among the evaluated genotypes. Allotetraploid BatDur1 had the lowest thrips-inflicted damage at each week post thrips release, while diploid A. batizocoi accession K9484 and A. duranensis accession V14167 had reduced feeding damage one week post thrips release, and diploids A. valida accession GK30011 and A. batizocoi had reduced feeding damage three weeks post thrips releasethan the others. Overall, plausible TSWV resistance in diploid species and their allotetraploid hybrids was characterized by reduced percent TSWV infection, virus accumulation, and feeding severity. Furthermore, a few diploids and tetraploid hybrids displayed antibiosis against thrips. These results document evidence for resistance against TSWV and thrips in wild diploid Arachis species and peanut-compatible-induced allotetraploids.

Characterization of gene expression patterns in response to an orthotospovirus infection between two diploid peanut species and their hybrid.

Tomato spotted wilt orthotospovirus (TSWV) transmitted by thrips causes significant yield loss in peanut (Arachis hypogaea L.) production. Use of peanut cultivars with moderate field resistance has been critical for TSWV management. However, current TSWV resistance is often not adequate, and the availability of sources of tetraploid resistance to TSWV is very limited. Allotetraploids derived by crossing wild diploid species could help introgress alleles that confer TSWV resistance into cultivated peanut. Thrips-mediated TSWV screening identified two diploids and their allotetraploid possessing the AA, BB, and AABB genomes Arachis stenosperma V10309, Arachis valida GK30011, and [A. stenosperma × A. valida]4x (ValSten1), respectively. These genotypes had reduced TSWV infection and accumulation in comparison with peanut of pure cultivated pedigree. Transcriptomes from TSWV-infected and non-infected samples from A. stenosperma, A. valida, and ValSten1 were assembled, and differentially expressed genes (DEGs) following TSWV infection were assessed. There were 3,196, 8,380, and 1,312 significant DEGs in A. stenosperma, A. valida, and ValSten1, respectively. A higher proportion of genes decreased in expression following TSWV infection for A. stenosperma and ValSten1, whereas a higher proportion of genes increased in expression following infection in A. valida. The number of DEGs previously annotated as defense-related in relation to abiotic and biotic stress was highest in A. valida followed by ValSten1 and A. stenosperma. Plant phytohormone and photosynthesis genes also were differentially expressed in greater numbers in A. valida followed by ValSten1 and A. stenosperma, with over half of those exhibiting decreases in expression.

Characterizing the vector competence of Aphis gossypii, Myzus persicae and Aphis craccivora (Hemiptera: Aphididae) to transmit cotton leafroll dwarf virus to cotton in the United States.

Cotton leafroll dwarf virus (CLRDV) is a yield-limiting, aphid-transmitted virus that was identified in cotton, Gossypium hirsutum L., in the United States of America in 2017. CLRDV is currently classified in the genus Polerovirus, family Solemoviridae. Although 8 species of aphids (Hemiptera: Aphididae) are reported to infest cotton, Aphis gossypii Glover is the only known vector of CLRDV to this crop. Aphis gossypii transmits CLRDV in a persistent and nonpropagative manner, but acquisition and retention times have only been partially characterized in Brazil. The main objectives of this study were to characterize the acquisition access period, the inoculation access period, and retention times for a U.S. strain of CLRDV and A. gossypii population. A sub-objective was to test the vector competence of Myzus persicae Sulzer and Aphis craccivora Koch. In our study, A. gossypii apterous and alate morphs were able to acquire CLRDV in 30 min and 24 h, inoculate CLRDV in 45 and 15 min, and retain CLRDV for 15 and 23 days, respectively. Neither M. persicae nor A. craccivora acquired or transmitted CLRDV to cotton.

Managing Nutrition Impact Symptoms in Cancer Cachexia: A Case Series and Mini Review.

Malnutrition is common in cancer patients and can occur throughout a patient's disease course. The contributors to the clinical syndrome of cancer cachexia are often multifactorial, and produced by the cancer and associated pro-inflammatory response. Since cancer cachexia is a multifactorial syndrome, a multimodal therapeutic approach is ideal. A key component of therapy is identifying and managing symptom barriers to adequate oral intake, known as nutritional impact symptoms (NIS). NIS are associated with reduced intake and weight loss in patients with advanced cancer, and aggregate NIS are a predictor of survival in patients with Head and Neck Cancer and in patients undergoing surgery for esophageal cancer. Currently, there are no guidelines regarding the specific management of NIS in oncology patients. Experience from specialist centers suggest relatively simple assessments and inexpensive interventions are available for the diagnosis and treatment of NIS. We present three patient cases from a cachexia clinic, where NIS management decreased symptom burden and improved clinical outcomes such as weight and physical performance.

A Review on Transcriptional Responses of Interactions between Insect Vectors and Plant Viruses.

This review provides a synopsis of transcriptional responses pertaining to interactions between plant viruses and the insect vectors that transmit them in diverse modes. In the process, it attempts to catalog differential gene expression pertinent to virus-vector interactions in vectors such as virus reception, virus cell entry, virus tissue tropism, virus multiplication, and vector immune responses. Whiteflies, leafhoppers, planthoppers, and thrips are the main insect groups reviewed, along with aphids and leaf beetles. Much of the focus on gene expression pertinent to vector-virus interactions has centered around whole-body RNA extraction, whereas data on virus-induced tissue-specific gene expression in vectors is limited. This review compares transcriptional responses in different insect groups following the acquisition of non-persistent, semi-persistent, and persistent (non-propagative and propagative) plant viruses and identifies parallels and divergences in gene expression patterns. Understanding virus-induced changes in vectors at a transcriptional level can aid in the identification of candidate genes for targeting with RNAi and/or CRISPR editing in insect vectors for management approaches.

Prospective Alternate Hosts of an Emerging Polerovirus in Cotton Landscapes in the Southeastern United States.

The identification of alternate hosts that can act as virus inoculum sources and vector reservoirs in the landscape is critical to understanding virus epidemics. Cotton leafroll dwarf virus (CLRDV) is a serious pathogen in cotton production and is transmitted by the cotton/melon aphid, Aphis gossypii, in a persistent, circulative, and non-propagative manner. CLRDV was first reported in the United States in Alabama in 2017, and thereafter in several cotton-producing states. CLRDV has since established itself in the southeastern United States. The role of alternate hosts in CLRDV establishment is not clear. Fourteen common plant species in the landscape, including crops, weeds, and ornamentals (cotton, hollyhock, marshmallow, country mallow, abutilon, arrowleaf sida, okra, hibiscus, squash, chickpea, evening primrose, henbit, Palmer amaranth, and prickly sida) were tested as potential alternate hosts of CLRDV along with an experimental host (Nicotiana benthamiana) via aphid-mediated transmission assays. CLRDV was detected following inoculation in hibiscus, okra, N. benthamiana, Palmer amaranth, and prickly sida by RT-PCR, but not in the others. CLRDV accumulation determined by RT-qPCR was the highest in N. benthamiana compared with cotton and other hosts. However, aphids feeding on CLRDV-infected prickly sida, hibiscus, and okra alone were able to acquire CLRDV and back-transmit it to non-infected cotton seedlings. Additionally, some of the alternate CLRDV hosts supported aphid development on par with cotton. However, in a few instances, aphid fitness was reduced when compared with cotton. Overall, this study demonstrated that plant hosts in the agricultural landscape can serve as CLRDV inoculum sources and as aphid reservoirs and could possibly play a role in the reoccurring epidemics of CLRDV in the southeastern United States.