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The worldwide population is ageing, alongside an increase in cancer incidence rates. Over the past 10 years, there has been huge progress in the field of oncology with earlier diagnosis and an expansion of treatment options, leading to a growing number of older people living with cancer. That has meant that caring for older patients with cancer is now part of day-to-day oncology practices. This cohort often has geriatric syndromes and a higher prevalence of frailty and complex needs and preparing our clinical services to optimise care for these patients is essential. Whilst it is widely accepted that comprehensive geriatric assessments are of benefit to patients, only a small proportion of patients can access these through specialised teams during their cancer care. In the past few years there has been significant progress in this field throughout the United Kingdom (UK). The goal of this review is to inform other health care systems how to learn from what has been done in the UK. This paper provides an update from our previous review in 2020, detailing the new services being implemented and made available to patients and an expansion in the number of new pilot teams and research projects/trials throughout the four nations of the UK., Competing Interests: Declaration of Competing Interest Mark Baxter reports a relationship with Servier Monde that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Mark Baxter reports a relationship with Ipsen that includes: speaking and lecture fees and travel reimbursement. Mark Baxter reports a relationship with Bristol Myers Squibb Co that includes: speaking and lecture fees. Mark Baxter reports a relationship with Merck Sharp & Dohme UK Ltd. that includes: speaking and lecture fees. Kirsty Balachandran reports a relationship with Bristol Myers Squibb Co that includes: speaking and lecture fees. Anne Barrell reports a relationship with Roche that includes: travel reimbursement. Anne Barrell reports a relationship with Bristol Myers Squibb Co that includes: speaking and lecture fees. Anne Barrell reports a relationship with Novartis AG that includes: speaking and lecture fees. Nicolo Matteo Luca Battisti reports a relationship with Pfizer Inc. that includes: board membership, speaking and lecture fees, and travel reimbursement. Nicolo Matteo Luca Battisti reports a relationship with Abbott that includes: board membership. Nicolo Matteo Luca Battisti reports a relationship with Sanofi that includes: board membership and speaking and lecture fees. Nicolo Matteo Luca Battisti reports a relationship with Astellas Pharma Inc. that includes: board membership. Nicolo Matteo Luca Battisti reports a relationship with Exact Sciences Corporation that includes: travel reimbursement. Nicolo Matteo Luca Battisti reports a relationship with Eli Lilly and Company that includes: speaking and lecture fees and travel reimbursement. Nicolo Matteo Luca Battisti reports a relationship with AbbVie Inc. that includes: speaking and lecture fees. Nicolo Matteo Luca Battisti reports a relationship with Roche that includes: speaking and lecture fees. Nicolo Matteo Luca Battisti reports a relationship with Servier Monde that includes: speaking and lecture fees. Nicolo Matteo Luca Battisti reports a relationship with Gilead Sciences Inc. that includes: speaking and lecture fees. Nicolo Matteo Luca Battisti reports a relationship with AstraZeneca Pharmaceuticals LP that includes: speaking and lecture fees. Kwok-Leung Cheung reports a relationship with Roche that includes: consulting or advisory. Kwok-Leung Cheung reports a relationship with Cancers that includes: travel reimbursement. Helen Brown reports a relationship with Roche that includes: funding grants. Fabio Gomes reports a relationship with AstraZeneca Pharmaceuticals LP that includes: speaking and lecture fees and travel reimbursement. Fabio Gomes reports a relationship with Roche that includes: speaking and lecture fees and travel reimbursement. Fabio Gomes reports a relationship with Boehringer Ingelheim GmbH that includes: speaking and lecture fees and travel reimbursement. Fabio Gomes reports a relationship with Pfizer Inc. that includes: speaking and lecture fees and travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Aims: There is a need to consolidate reporting guidance for nutrition randomised controlled trial (RCT) protocols. The reporting completeness in nutrition RCT protocols and study characteristics associated with adherence to SPIRIT and TIDieR reporting guidelines are unknown. We, therefore, assessed reporting completeness and its potential predictors in a random sample of published nutrition and diet-related RCT protocols., Methods: We conducted a meta-research study of 200 nutrition and diet-related RCT protocols published in 2019 and 2021 (aiming to consider periods before and after the start of the COVID pandemic). Data extraction included bibliometric information, general study characteristics, compliance with 122 questions corresponding to items and subitems in the SPIRIT and TIDieR checklists combined, and mention to these reporting guidelines in the publications. We calculated the proportion of protocols reporting each item and the frequency of items reported for each protocol. We investigated associations between selected publication aspects and reporting completeness using linear regression analysis., Results: The majority of protocols included adults and elderly as their study population (n = 73; 36.5%), supplementation as intervention (n = 96; 48.0%), placebo as comparator (n = 89; 44.5%), and evaluated clinical status as the outcome (n = 80; 40.0%). Most protocols described a parallel RCT (n = 188; 94.0%) with a superiority framework (n = 141; 70.5%). Overall reporting completeness was 52.0% (SD = 10.8%). Adherence to SPIRIT items ranged from 0% (n = 0) (data collection methods) to 98.5% (n = 197) (eligibility criteria). Adherence to TIDieR items ranged from 5.5% (n = 11) (materials used in the intervention) to 98.5% (n = 197) (description of the intervention). The multivariable regression analysis suggests that a higher number of authors [β = 0.53 (95%CI: 0.28-0.78)], most recent published protocols [β = 3.19 (95%CI: 0.24-6.14)], request of reporting guideline checklist during the submission process by the journal [β = 6.50 (95%CI: 2.56-10.43)] and mention of SPIRIT by the authors [β = 5.15 (95%CI: 2.44-7.86)] are related to higher reporting completeness scores., Conclusions: Reporting completeness in a random sample of 200 diet or nutrition-related RCT protocols was low. Number of authors, year of publication, self-reported adherence to SPIRIT, and journals' endorsement of reporting guidelines seem to be positively associated with reporting completeness in nutrition and diet-related RCT protocols., Competing Interests: Conflicts of interest Flávia Moraes Silva received a postdoctoral fellowship from COPPETEC Foundation. Michael Maia Schlussel, Shona Kirtley, Jennifer A de Beyer and Gary Collins are funded by Cancer Research UK (grant C49297/A27294). Matthew J Page is supported by an Australian Research Council Discovery Early Career Researcher Award (DE200101618). Colby Vorland has received honoraria from The Obesity Society and the Alliance for Potato Research and Education, and his university has received funds to support his research from: National Cattlemen's Beef Association; Alliance for Potato Research and Education; the Gordon and Betty Moore Foundation; and NIH. All authors work directly or have collaborations with the EQUATOR Network, an international initiative that seeks to improve the reliability and value of published health research literature by promoting transparent and accurate reporting and wider use of robust reporting guidelines., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: Checkpoint inhibitors (CPI) are widely used across different tumour types in older cancer patients. The ELDERS study investigated primarily the safety of CPI in older patients, and secondarily its impact on health-related quality of life (HRQoL), comparing older and younger patients. Here we describe the results from its secondary aim., Materials and Methods: This was an observational, mixed methods study, consisting of questionnaires and qualitative interviews. Patients completed the EORTC QLQ-C30 at baseline and at three-monthly reviews (up to four over the planned 12 months on study)., Results: One hundred and forty patients, 70 in each age cohort (older: ≥70 years of age, younger: <70 years of age), were recruited. Twenty-four patients, 12 in each age cohort, were interviewed. The mean baseline EORTC QLQ-C30 score was 65/100 for both cohorts combined, and the score for the full QLQ-C30 assessment was 78/100 and 75/100 for older and younger, respectively. The physical functioning score was the only subscale to change significantly between baseline and the first and second reviews (p = 0.03 and 0.04, respectively), resulting from some improvement in the mean score (from baseline) within the younger cohort and some decline within the older cohort. However, when focusing on each cohort separately, the change over time was not statistically significant for either. Two main themes from the interviews were 'expectations' (thoughts about treatment before commencing) and 'experience' (lived experience during treatment)., Discussion: Quantitatively, there was no difference in the effect of CPIs on HRQoL between the cohorts, although qualitative data from interviews suggested that there were some experiential differences. People in the older cohort were less likely to seek additional information about CPIs and were more likely to report side effects. In terms of both 'expectations' and 'experience,' the older cohort was a heterogenous group, highlighting that an individualised approach is needed when supporting this group. This study shows that older patients can be reassured that immunotherapy is unlikely to negatively impact their HRQoL more than younger patients, and it should be considered a viable treatment option., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Immune checkpoint inhibitors (ICIs) became a treatment option in most tumor types and improved survival in patients with cancer in the last decade. Older patients with cancer are underrepresented in the pivotal clinical trials with ICIs. Older patients with cancer often have significant comorbidities and geriatric syndromes like frailty, which can complicate cancer care and treatment decisions. Frailty is among the most prevalent geriatric syndromes in patients with cancer and could lead to inferior survival and a higher risk of complications in patients treated with chemotherapy. However, the effect of frailty on the efficacy and safety of ICIs is understudied. This review focuses on the available evidence regarding the association between frailty and ICI efficacy and safety. Although the survival benefits of ICIs have generally been shown to be independent of age, the available real-world data has generally suggested higher rates of immune-related adverse events (irAEs) and treatment discontinuation in older patients. While international organizations recommend conducting a comprehensive geriatric assessment CGA to assess and address frailty before the start of anti-cancer therapies, an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher is frequently used in clinical practice as synonymous with frailty, albeit with significant limitations. The available data has generally demonstrated diminished ICI efficacy in patients with an ECOG 2 or higher compared to patients with better performance status, while the incidence of high-grade irAEs were similar. Whilst evidence regarding outcomes with ICI in older patients and in those with sub-optimal performance status is growing, there is very limited data specifically evaluating the role of frailty with ICIs. These studies found a shortened overall survival, yet no evidence of a lower response rate to ICIs. These patients experienced more AEs, but they did not necessarily have a higher incidence of irAEs., Competing Interests: Conflict of Interest The authors declare no potential conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The integration of digital health technologies in geriatric oncology has the potential to enhance patient care and self-management. This review article discusses the applications of these technologies, including teleassessment, telemonitoring, and teleintervention, within geriatric oncology, and evaluates their potential to improve cancer care and patient outcomes. We also review challenges to the implementation of digital health technologies among populations of older patients with cancer. The article provides a perspective for clinicians, researchers, policymakers, and patients on the integration and utilisation of digital health technologies in current geriatric oncology practice., Competing Interests: Declaration of Competing Interest Colm Mac Eochagain: None. Nicolás María González Senac: None. Mukul Roy: None. Andrea Ciccone: None. Beatriz Contreras: None. Rogelio Velasco: None. Melody Schiaffino: None. Giuseppe Dario Testa: None. Joana Marinho: None. Adolfo Gonzales Serrano: None. Mercedes Cavanagh: None. Fabio Gomes: Dr. Gomes reports grants from Pfizer, personal fees from Roche, personal fees from BMS, personal fees from AstraZeneca, personal fees from Takeda, outside the submitted work., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: The COVID-19 pandemic impacted the care and experiences of people with cancer, but it presented an opportunity to improve the delivery of outpatient care post-pandemic., Materials and Methods: We performed an observational cross-sectional study with people with lung cancer throughout the COVID-19 pandemic. A survey investigated patients' experiences and preferences regarding the delivery of cancer care to plan for post-pandemic care, as well as the pandemic's impact on their functional status (physical and psycho-social), exploring the role of age and frailty., Results: Amongst 282 eligible participants, 88%, 86%, and 59% of patients reported feeling appropriately supported during the pandemic by their cancer centre, friends/family, and primary care services, respectively. Remote oncology consultations were delivered to 90% of patients during the pandemic, of which 3% did not meet patients' expectations. Regarding post-pandemic outpatient care preferences, face-to-face appointments were preferred by 93% for the first appointment, by 64% when discussing imaging results, and by 60% for reviews during anti-cancer treatments. Older patients aged 70 years and above were more likely to favour face-to-face appointments (p = 0.007), regardless of their frailty status. Patient preferences changed over time, with the more recent participants preferring remote appointments during anti-cancer treatments (p = 0.0278). Regarding the pandemic's impact, abnormal levels of anxiety and depression were found in 16% and 17% of patients, respectively. Younger patients experienced higher abnormal levels of anxiety and depression (p = 0.036, p = 0.021). Amongst the older sub-group, those with frailty had higher levels of anxiety and depression (p < 0.001). Amongst all participants, 54% reported a considerable negative impact from the pandemic on different aspects of their daily life, particularly emotional and psychological health and sleep patterns, which were more marked in younger patients and the older sub-group with frailty. Older patients without frailty reported the least impact on their functional status., Discussion: There is a need for more personalised outpatient consultation options during cancer care. Whilst there is a preference for face-to-face consultations for older patients, following the pandemic there is a growing acceptance of remote consultations particularly during anti-cancer treatment. Older patients with lung cancer without frailty were less affected by the pandemic than those with frailty and younger patients, requiring less support from healthcare services., Competing Interests: Declaration of Competing Interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cattle ranching is the largest driver of deforestation in the Brazilian Amazon. The rainforest-to-pasture conversion affects the methane cycle in upland soils, changing it from sink to source of atmospheric methane. However, it remains unknown if management practices could reduce the impact of land-use on methane cycling. In this work, we evaluated how pasture management can regulate the soil methane cycle either by maintaining continuous grass coverage on pasture soils, or by liming the soil to amend acidity. Methane fluxes from forest and pasture soils were evaluated in moisture-controlled greenhouse experiments with and without grass cover (Urochloa brizantha cv. Marandu) or liming. We also assessed changes in the soil microbial community structure of both bare (bulk) and rhizospheric pasture soils through high throughput sequencing of the 16S rRNA gene, and quantified the methane cycling microbiota by their respective marker genes related to methane generation (mcrA) or oxidation (pmoA). The experiments used soils from eastern and western Amazonia, and concurrent field studies allowed us to confirm greenhouse data. The presence of a grass cover not only increased methane uptake by up to 35% in pasture soils, but also reduced the abundance of the methane-producing community. In the grass rhizosphere this reduction was up to 10-fold. Methane-producing archaea belonged to the genera Methanosarcina sp., Methanocella sp., Methanobacterium sp., and Rice Cluster I. Further, we showed that soil liming to increasing pH compromised the capacity of forest and pasture soils to be a sink for methane, and instead converted formerly methane-consuming forest soils to become methane sources in only 40-80 days. Liming reduced the relative abundance of Beijerinckiacea family in forest soils, which account for many known methanotrophs. Our results demonstrate that pasture management that maintains grass coverage can mitigate soil methane emissions, compared to bare (bulk) pasture soil., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare.

Introduction: Patients with thoracic malignancies are at increased risk for mortality from coronavirus disease 2019 (COVID-19), and a large number of intertwined prognostic variables have been identified so far., Methods: Capitalizing data from the Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry, a global study created with the aim of describing the impact of COVID-19 in patients with thoracic malignancies, we used a clustering approach, a fast-backward step-down selection procedure, and a tree-based model to screen and optimize a broad panel of demographics and clinical COVID-19 and cancer characteristics., Results: As of April 15, 2021, a total of 1491 consecutive eligible patients from 18 countries were included in the analysis. With a mean observation period of 42 days, 361 events were reported with an all-cause case fatality rate of 24.2%. The clustering procedure screened 73 covariates in 13 clusters. A further multivariable logistic regression for the association between clusters and death was performed, resulting in five clusters significantly associated with the outcome. The fast-backward step-down selection procedure then identified the following seven major determinants of death: Eastern Cooperative Oncology Group-performance status (ECOG-PS) (OR = 2.47, 1.87-3.26), neutrophil count (OR = 2.46, 1.76-3.44), serum procalcitonin (OR = 2.37, 1.64-3.43), development of pneumonia (OR = 1.95, 1.48-2.58), C-reactive protein (OR = 1.90, 1.43-2.51), tumor stage at COVID-19 diagnosis (OR = 1.97, 1.46-2.66), and age (OR = 1.71, 1.29-2.26). The receiver operating characteristic analysis for death of the selected model confirmed its diagnostic ability (area under the receiver operating curve = 0.78, 95% confidence interval: 0.75-0.81). The nomogram was able to classify the COVID-19 mortality in an interval ranging from 8% to 90%, and the tree-based model recognized ECOG-PS, neutrophil count, and c-reactive protein as the major determinants of prognosis., Conclusions: From 73 variables analyzed, seven major determinants of death have been identified. Poor ECOG-PS was found to have the strongest association with poor outcome from COVID-19. With our analysis, we provide clinicians with a definitive prognostication system to help determine the risk of mortality for patients with thoracic malignancies and COVID-19., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The ongoing coronavirus disease 2019 (COVID-19) pandemic has affected millions of people in over 180 territories, causing a significant impact on healthcare systems globally. Older adults, as well as people living with cancer, appear to be particularly vulnerable to COVID-19 related morbidity and mortality, which means that older adults with cancer are an especially high-risk population. This has led to significant changes in the way geriatric oncologists provide care to older patients, including the implementation of novel methods for clinical visits, interruptions or delays in procedures, and modification of therapeutic strategies, both in the curative and palliative settings. In this manuscript, we provide a global overview of the perspectives of geriatric oncology providers from countries across Europe, America, and Asia, regarding the adaptive strategies utilized to continue providing high quality care for older patients with cancer during the COVID-19 pandemic. Through these perspectives, we attempt to show that, although each country and setting has specific issues, we all face similar challenges when providing care for our older patients with cancer during these difficult times., Competing Interests: Declaration of Competing Interest Dr. Battisti has received travel grants and speaker fees from Pfizer and travel grants from Genomic Health. Dr. Loh serves as a consultant to Pfizer and Seattle Genetics. Dr. Loh is supported by the Wilmot Research Fellowship Award and National Cancer Institute (K99CA237744). Dr. Neuendorff has received honoraria and travel support by Janssen-Cilag, Medac, and Jazz Pharmazeutical. Dr. Mian reports Honoraria/Consultancy fees from Amgen, Celgene, Takeda, Janssen, Sanofi. All other authors have no financial conflicts of interest to disclose., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Studies of older patients with colorectal cancer(CRC) have found inconsistent results about the correlation of various comorbidities with overall survival(OS) and treatment tolerance. To refine our understanding, we evaluated this correlation using the Cumulative Illness Rating Scale-Geriatric(CIRS-G) and heat maps to identify subgroups with the highest impact., Methods: We retrospectively reviewed 153 patients aged 65 years and older with stage IV CRC undergoing chemotherapy. We calculated CIRS-G scores, and a Total Risk Score(TRS) derived from a previous heat map study. The association between CIRS-G scores/TRS and OS, unplanned hospitalizations, and chemotoxicity was examined by the Cox proportional hazards model., Results: Median age was 71 years. Median MAX2 score of chemotherapies was 0.134(0.025-0.231). The most common comorbidities were vascular(79.8%), eye/ear/nose/throat(68%), and respiratory disease(52.4%). Median OS was 25.1 months(95% confidence interval: 21.2-27.6). In univariate analysis, ECOG PS ≥ 2(HR 1.86(1.1-3.17), p = 0.019), poorly differentiated histology(HR 2.03(1.27-3.25), p = 0.003), primary site(rectum vs colon)(HR 0.58 (0.34-0.98), p = 0.04), age at diagnosis(HR per 5y 1.20 (1.04-1.39), p = 0.012), and number of CIRS-G grade 4 comorbidities(HR 1.86 (1.1-3.17), p = 0.019) were associated with OS. In multivariate analysis, the number of CIRS-G grade 4 comorbidities lost significance, although it retained it in the subgroup of patients with colon cancer. Conversely, the TRS was associated with OS in patients with rectal cancer. No association of comorbidity with unplanned hospitalization or chemotoxicity was observed., Conclusions: In older adults with metastatic CRC, the number of CIRS-G grade 4 comorbidities was associated with worse OS but no specific CIRS-G category was independently associated with OS, unplanned hospitalization, or toxicities., (Copyright © 2019. Published by Elsevier Ltd.)

This case report discusses the successful endodontic treatment of an open apex maxillary right permanent central incisor that had been avulsed and incorrectly replanted in a 7-year-old patient. The tooth was carefully re-extracted followed by cleaning of the alveolar socket and immediate replantation. However, pulp necrosis was diagnosed, and regenerative endodontic treatment was performed. The root canal system was disinfected by passive ultrasonic irrigation with 2.5% sodium hypochlorite. At the first visit, the tooth was repositioned and immobilized with an appropriate semirigid splint. After 14 days, the splint was removed, and the diagnosis of pulp necrosis was confirmed by thermal testing. The root canal was emptied, disinfected, and filled with calcium hydroxide paste, which was left in place for 7 days. At the third visit, calcium hydroxide was removed with hand files and passive ultrasonic irrigation, and the canal was filled with a mixture of double antibiotic paste (metronidazole/ciprofloxacin) and zinc oxide. The antibiotic paste was left in place for 30 days. At the final visit, the paste was removed and the periapical area stimulated with a #80 K-file to encourage clot formation within the pulp cavity. A mineral trioxide aggregate paste cervical plug was placed, and the tooth was restored with glass ionomer cement. Clinical and imaging (radiographic and tomographic) follow-up at 3, 6, 12, and 36 months showed endodontic success with continued root formation., (Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Classic galactosemia is an inborn error of metabolism caused by deleterious mutations in the GALT gene. A number of evidences indicate that the galactose-1-phosphate accumulation observed in patient cells is a cause of toxicity in this disease. Nevertheless, the consequent molecular events caused by the galactose-1-phosphate accumulation remain elusive. Here we show that intracellular inorganic phosphate levels decreased when yeast models of classic galactosemia were exposed to galactose. The decrease in phosphate levels is probably due to the trapping of phosphate in the accumulated galactose-1-phosphate since the deletion of the galactokinase encoding gene GAL1 suppressed this phenotype. Galactose-induced phosphate depletion caused an increase in glycogen content, an expected result since glycogen breakdown by the enzyme glycogen phosphorylase is dependent on inorganic phosphate. Accordingly, an increase in intracellular phosphate levels suppressed the galactose effect on glycogen content and conferred galactose tolerance to yeast models of galactosemia. These results support the hypothesis that the galactose-induced decrease in phosphate levels leads to toxicity in galactosemia and opens new possibilities for the development of better treatments for this disease., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In this study, we quantified the ability of opioids present in biological samples to activate the μ-opioid receptor and TLR4 using cell-based assays. Each assay was standardised, in the presence of plasma, using morphine, its μ receptor-active metabolite morphine-6 glucuronide (M6G) and its μ receptor-inactive, but TLR4-active metabolite morphine-3 glucuronide (M3G). Specificity was verified using antagonists. Morphine- and M6G-spiked plasma samples exhibited μ receptor activation, which M3G-spiked plasma lacked. In contrast, M3G showed moderate but consistent activation of TLR-4. Plasma samples were collected at a number of time points from mice administered morphine (1 or 10mg/kg every 12h for 3days) or saline. Morphine administration led to intermittent μ receptor activation, reversed by μ receptor antagonists, and to TRL4 activation at time points where M3G is measured in plasma. Interestingly, this protocol of morphine administration also led to TLR4-independent NF-κB activation, at time points where M3G was not detected, presumably via elevation of circulating cytokines including, but not limited to, TNFα. Circulating TNFα was increased after three days of morphine administration, and TNFα mRNA elevated in the spleen of morphine-treated mice., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The determination of both the water-soluble and lipid-soluble vitamin D compounds in human biological fluids is necessary to illuminate potentially significant biochemical mechanisms. The lack of analytical methods to quantify the water-soluble forms precludes studies on their role and biological functions; currently available liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods are able to determine only a single sulfated form of Vitamin D. We describe here a highly sensitive and specific LC-MS/MS method for the quantification of four sulfated forms of vitamin D: vitamins D2- and D3-sulfate (D2-S and D3-S) and 25-hydroxyvitamin D2- and D3-sulfate (25(OH)D2-S and 25(OH)D3-S). A comparative evaluation showed that the ionization efficiencies of underivatized forms in negative ion mode electrospray ionisation (ESI) are superior to those of the derivatized (using 4-phenyl-l,2,4-triazoline-3,5-dione (PTAD)) forms in positive ion mode ESI. Separation was optimised to minimise co-elution with endogenous matrix compounds, thereby reducing ion suppression/enhancement effects. Isotopically labelled analogues of each compound were used as internal standards to correct for ion suppression/enhancement effects. The method was validated and then applied for the analysis of breastmilk and human serum. The detection limits, repeatability standard deviations, and recoveries ranged from 0.20 to 0.28fmol, 2.8 to 10.2%, and 81.1 to 102%, respectively., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Milk is an important source of nutrients for various risk populations, including infants. The accurate measurement of vitamin D in milk is necessary to provide adequate supplementation advice for risk groups and to monitor regulatory compliance. Currently used liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods are capable of measuring only four analogues of vitamin D in unfortified milk. We report here an accurate quantitative analytical method for eight analogues of vitamin D: Vitamin D2 and D3 (D2 and D3), 25-hydroxy D2 and D3, 24,25-dihydroxy D2 and D3, and 1,25-dihydroxyD2 and D3. In this study, we compared saponification and protein precipitation for the extraction of vitamin D from milk and found the latter to be more effective. We also optimised the pre-column derivatisation using 4-phenyl-l,2,4-triazoline-3,5-dione (PTAD), to achieve the highest sensitivity and accuracy for all major vitamin D forms in milk. Chromatography was optimised to reduce matrix effects such as ion-suppression, and the matrix effects were eliminated using co-eluting stable isotope labelled internal standards for the calibration of each analogue. The analogues, 25-hydroxyD3 (25(OH)D3) and its epimer (3-epi-25(OH)D3) were chromatographically resolved, to prevent over-estimation of 25(OH)D3. The method was validated and subsequently applied for the measurement of total vitamin D levels in human, cow, mare, goat and sheep milk samples. The detection limits, repeatability standard deviations, and recovery ranges were from 0.2 to 0.4 femtomols, 6.30-13.5%, and 88.2-105%, respectively., (Copyright © 2015 Elsevier B.V. All rights reserved.)

To achieve WHO's target to halt the rise in obesity and diabetes, dramatic actions are needed to improve the healthiness of food environments. Substantial debate surrounds who is responsible for delivering effective actions and what, specifically, these actions should entail. Arguments are often reduced to a debate between individual and collective responsibilities, and between hard regulatory or fiscal interventions and soft voluntary, education-based approaches. Genuine progress lies beyond the impasse of these entrenched dichotomies. We argue for a strengthening of accountability systems across all actors to substantially improve performance on obesity reduction. In view of the industry opposition and government reluctance to regulate for healthier food environments, quasiregulatory approaches might achieve progress. A four step accountability framework (take the account, share the account, hold to account, and respond to the account) is proposed. The framework identifies multiple levers for change, including quasiregulatory and other approaches that involve government-specified and government-monitored progress of private sector performance, government procurement mechanisms, improved transparency, monitoring of actions, and management of conflicts of interest. Strengthened accountability systems would support government leadership and stewardship, constrain the influence of private sector actors with major conflicts of interest on public policy development, and reinforce the engagement of civil society in creating demand for healthy food environments and in monitoring progress towards obesity action objectives., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Despite being the main insect pest on soybean crops in the Americas, very few studies have approached the general biology of the lepidopteran Anticarsia gemmatalis and there is a paucity of studies with embryo formation and yolk mobilization in this species. In the present work, we identified an acid phosphatase activity in the eggs of A. gemmatalis (agAP) that we further characterized by means of biochemistry and cell biology experiments. By testing several candidate substrates, this enzyme proved chiefly active with phosphotyrosine; in vitro assays suggested a link between agAP activity and dephosphorylation of egg yolk phosphotyrosine. We also detected strong activity with endogenous and exogenous short chain polyphosphates (PolyP), which are polymers of phosphate residues involved in a number of physiological processes. Both agAP activity and PolyP were shown to initially concentrate in small vesicles clearly distinct from typically larger yolk granules, suggesting subcellular compartmentalization. As PolyP has been implicated in inhibition of yolk proteases, we performed in vitro enzymatic assays with a cysteine protease to test whether it would be inhibited by PolyP. This cysteine protease is prominent in Anticarsia egg homogenates. Accordingly, short chain PolyP was a potent inhibitor of cysteine protease. We thereby suggest that PolyP hydrolysis by agAP is a triggering mechanism of yolk mobilization in A. gemmatalis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

PhoB/PhoR is a two-component system originally described as involved in inorganic phosphate (Pi) transport and metabolism under Pi limitation. In order to disclose other roles of this system, a proteomic analysis of Vibrio cholerae 569BSR and its phoB/phoR mutant under high Pi levels was performed. Most of the proteins downregulated by the mutant have roles in energy production and conversion and in amino acid transport and metabolism. In contrast, the phoB/phoR mutant upregulated genes mainly involved in adaptation to atypical conditions, indicating that the absence of a functional PhoB/PhoR caused increased expression of a number of genes from distinct stress response pathways. This might be a strategy to overcome the lack of RpoS, whose expression in the stationary phase cells of V. cholerae seems to be controlled by PhoB/PhoR. Moreover, compared to the wild-type strain the phoB/phoR mutant presented a reduced cell density at stationary phase of culture in Pi abundance, lower resistance to acid shock, but higher tolerance to thermal and osmotic stresses. Together our findings show, for the first time, the requirement of PhoB/PhoR for full growth under high Pi level and for the accumulation of RpoS, indicating that PhoB/PhoR is a fundamental system for the biology of V. cholerae., Biological Significance: Certain V. cholerae strains are pathogenic to humans, causing cholera, an acute dehydrating diarrhoeal disease endemic in Southern Asia, parts of Africa and Latin America, where it has been responsible for significant mortality and economical damage. Its ability to grow within distinct niches is dependent on gene expression regulation. PhoB/PhoR is a two-component system originally described as involved in inorganic phosphate (Pi) transport and metabolism under Pi limitation. However, Pho regulon genes also play roles in virulence, motility and biofilm formation, among others. In this paper we report that the absence of a functional PhoB/PhoR caused increased expression of a number of genes from distinct stress response pathways, in Pi abundance. Moreover, we showed, for the first time, that the interrelationship between PhoB-RpoS-(p)ppGpp-poly(P) in V. cholerae, is somewhat diverse from the model of inter-regulation between those systems, described in Escherichia coli. The V. cholerae dependence on PhoB/PhoR for the RpoS mediated stress response and cellular growth under Pi abundance, suggests that this system's roles are broader than previously thought., (Copyright © 2013. Published by Elsevier B.V.)

A simple and sensitive analytical method for simultaneous determination of anastrozole, bicalutamide, and tamoxifen as well as their synthetic impurities, anastrozole pentamethyl, bicalutamide 3-fluoro-isomer, and tamoxifen e-isomer, was developed and validated by using high performance liquid chromatography (HPLC). The separation was achieved on a Symmetry(®) C-8 column (100×4.6 mm i.d., 3.5 μm) at room temperature (±24 °C), with a mobile phase consisting of acetonitrile/water containing 0.18% N,N dimethyloctylamine and pH adjusted to 3.0 with orthophosphoric acid (46.5/53.5, v/v) at a flow rate of 1.0 mL min(-1) within 20 min. The detection was made at a wavelength of 270 nm by using ultraviolet (UV) detector. No interference peaks from excipients and relative retention time indicated the specificity of the method. The calibration curve showed correlation coefficients (r) >0.99 calculated by linear regression and analysis of variance (ANOVA). The limit of detection (LOD) and limit of quantitation (LOQ), respectively, were 2.2 and 6.7 μg mL(-1) for anastrozole, 2.61 and 8.72 μg mL(-1) for bicalutamide, 2.0 and 6.7 μg mL(-1) for tamoxifen, 0.06 and 0.22 μg mL(-1) for anastrozole pentamethyl, 0.02 and 0.07 μg mL(-1) for bicalutamide 3-fluoro-isomer, and 0.002 and 0.007 μg mL(-1) for tamoxifen e-isomer. Intraday and interday relative standard deviations (RSDs) were <2.0% (drugs) and <10% (degradation products) as well as the comparison between two different analysts, which were calculated by f test., (Copyright © 2012 Elsevier B.V. All rights reserved.)

In this work we characterized the degenerative process of ovarian follicles of the bug Rhodnius prolixus challenged with the non-entomopathogenic fungus Aspergillus niger. An injection of A. niger conidia directly into the hemocoel of adult R. prolixus females at the onset of vitellogenesis caused no effect on host lifespan but elicited a net reduction in egg batch size. Direct inspection of ovaries from the mycosed insects revealed that fungal challenge led to atresia of the vitellogenic follicles. Light microscopy and DAPI staining showed follicle shrinkage, ooplasm alteration and disorganization of the monolayer of follicle cells in the atretic follicles. Transmission electron microscopy of thin sections of follicle epithelium also showed nuclei with condensed chromatin, electron dense mitochondria and large autophagic vacuoles. Occurrence of apoptosis of follicle cells in these follicles was visualized by TUNEL labeling. Resorption of the yolk involved an increase in protease activities (aspartyl and cysteinyl proteases) which were associated with precocious acidification of yolk granules and degradation of yolk protein content. The role of follicle atresia in nonspecific host-pathogen associations and the origin of protease activity that led to yolk resorption are discussed., (Copyright © 2011 Elsevier Ltd. All rights reserved.)