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1.
Plant Biotechnol J ; 2024 May 07.
Article in English | MEDLINE | ID: mdl-38715250

ABSTRACT

MicroRNA169 (miR169) has been implicated in multi-stress regulation in annual species such as Arabidopsis, maize and rice. However, there is a lack of experimental functional and mechanistic studies of miR169 in plants, especially in perennial species, and its impact on plant growth and development remains unexplored. Creeping bentgrass (Agrostis stolonifera L.) is a C3 cool-season perennial turfgrass of significant environmental and economic importance. In this study, we generated both miR169 overexpression and knockdown transgenic creeping bentgrass lines. We found that miR169 acts as a positive regulator in abiotic stress responses but is negatively associated with plant growth and development, playing multiple critical roles in the growth and environmental adaptation of creeping bentgrass. These roles include differentiated spatial hormone accumulation patterns associated with growth and stress accommodation, elevated antioxidant activity that alleviates oxidative damage induced by stress, ion-channelling membrane components for maintaining homeostasis under saline conditions, and potential cross-talks with stress-regulating transcription factors such as AsHsfA and AsWRKYs. Our results unravel the role of miR169 in modulating plant development and stress responses in perennial grass species. This underlines the potential of manipulating miR169 to generate crop cultivars with desirable traits to meet diverse agricultural demands.

2.
Toxics ; 12(2)2024 Jan 26.
Article in English | MEDLINE | ID: mdl-38393201

ABSTRACT

Perfluorooctanesulfonate (PFOS) is a widespread environmental pollutant with a long half-life and clearly negative outcomes on metabolic diseases such as fatty liver disease and diabetes. Male and female Cyp2b-null and humanized CYP2B6-transgenic (hCYP2B6-Tg) mice were treated with 0, 1, or 10 mg/kg/day PFOS for 21 days, and surprisingly it was found that PFOS was retained at greater concentrations in the serum and liver of hCYP2B6-Tg mice than those of Cyp2b-null mice, with greater differences in the females. Thus, Cyp2b-null and hCYP2B6-Tg mice provide new models for investigating individual mechanisms for PFOS bioaccumulation and toxicity. Overt toxicity was greater in hCYP2B6-Tg mice (especially females) as measured by mortality; however, steatosis occurred more readily in Cyp2b-null mice despite the lower PFOS liver concentrations. Targeted lipidomics and transcriptomics from PFOS-treated Cyp2b-null and hCYP2B6-Tg mouse livers were performed and compared to PFOS retention and serum markers of toxicity using PCA. Several oxylipins, including prostaglandins, thromboxanes, and docosahexaenoic acid metabolites, are associated or inversely associated with PFOS toxicity. Both lipidomics and transcriptomics indicate PFOS toxicity is associated with PPAR activity in all models. GO terms associated with reduced steatosis were sexually dimorphic with lipid metabolism and transport increased in females and circadian rhythm associated genes increased in males. However, we cannot rule out that steatosis was initially protective from PFOS toxicity. Moreover, several transporters are associated with increased retention, probably due to increased uptake. The strongest associations are the organic anion transport proteins (Oatp1a4-6) genes and a long-chain fatty acid transport protein (fatp1), enriched in female hCYP2B6-Tg mice. PFOS uptake was also reduced in cultured murine hepatocytes by OATP inhibitors. The role of OATP1A6 and FATP1 in PFOS transport has not been tested. In summary, Cyp2b-null and hCYP2B6-Tg mice provided unique models for estimating the importance of novel mechanisms in PFOS retention and toxicity.

3.
J Med Internet Res ; 25: e47266, 2023 10 13.
Article in English | MEDLINE | ID: mdl-37831505

ABSTRACT

BACKGROUND: Innovative mobile health (mHealth) interventions can improve maternal knowledge, thereby supporting national efforts to reduce preventable maternal and child mortality in South Africa. Studies have documented a potential role for mobile video content to support perinatal health messaging, enhance maternal satisfaction, and overcome literacy barriers. Short, animated storytelling (SAS) is an innovative, emerging approach to mHealth messaging. OBJECTIVE: We aimed to measure the effect of SAS videos on maternal knowledge and user satisfaction for mothers enrolled in antenatal care programs at 2 public health facilities in the Tshwane District of South Africa. METHODS: We used a randomized controlled trial with a nested evaluation of user satisfaction. Participants were randomized 1:1 into Standard-of-Care (SOC) Control, and SAS Intervention groups. The intervention videos were delivered through WhatsApp, and 1 month later, participants responded to telephone surveys assessing their knowledge. The intervention group then participated in a nested evaluation of user satisfaction. RESULTS: We surveyed 204 participants. Of them, 49.5% (101/204) were aged between 25 and 34 years. Almost all participants self-identified as Black, with the majority (190/204, 93.2%) having completed secondary school. The mean overall knowledge score was 21.92/28. We observed a slight increase of 0.28 (95% uncertainty interval [UI] -0.58 to 1.16) in the overall knowledge score in the intervention arm. We found that those with secondary education or above scored higher than those with only primary education by 2.24 (95% UI 0.76-4.01). Participants aged 35 years or older also scored higher than the youngest age group (18-24 years) by 1.83 (95% CI 0.39-3.33). Finally, the nested user satisfaction evaluation revealed high maternal satisfaction (4.71/5) with the SAS video series. CONCLUSIONS: While the SAS videos resulted in high user satisfaction, measured knowledge gains were small within a participant population that was already receiving perinatal health messages through antenatal clinics. The higher knowledge scores observed in older participants with higher education levels suggest that boosting maternal knowledge in younger mothers with lower education levels should continue to be a public health priority in South Africa. Given the high maternal satisfaction among the SAS video-users in this study, policy makers should consider integrating similar approaches into existing, broad-reaching perinatal health programs, such as MomConnect, to boost satisfaction and potentially enhance maternal engagement. While previous studies have shown the promise of animated video health education, most of this research has been conducted in high-income countries. More research in underresourced settings is urgently needed, especially as access to mobile technology increases in the Global South. Future studies should explore the effect of SAS videos on maternal knowledge in hard-to-reach populations with limited access to antenatal care, although real-world logistical challenges persist when implementing studies in underresourced South African populations. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR202203673222680; https://tinyurl.com/362cpuny.


Subject(s)
Mothers , Parturition , Child , Humans , Female , Pregnancy , Aged , Adult , South Africa , Mothers/education , Prenatal Care , Personal Satisfaction
4.
Bioengineering (Basel) ; 10(8)2023 Aug 07.
Article in English | MEDLINE | ID: mdl-37627822

ABSTRACT

Pentagalloyl glucose (PGG) is currently being investigated as a non-surgical treatment for abdominal aortic aneurysms (AAAs); however, the molecular mechanisms of action of PGG on the AAA matrix components and the intra-luminal thrombus (ILT) still need to be better understood. To assess these interactions, we utilized peptide fingerprinting and molecular docking simulations to predict the binding of PGG to vascular proteins in normal and aneurysmal aorta, including matrix metalloproteinases (MMPs), cytokines, and fibrin. We performed PGG diffusion studies in pure fibrin gels and human ILT samples. PGG was predicted to bind with high affinity to most vascular proteins, the active sites of MMPs, and several cytokines known to be present in AAAs. Finally, despite potential binding to fibrin, PGG was shown to diffuse readily through thrombus at physiologic pressures. In conclusion, PGG can bind to all the normal and aneurysmal aorta protein components with high affinity, potentially protecting the tissue from degradation and exerting anti-inflammatory activities. Diffusion studies showed that thrombus presence in AAAs is not a barrier to endovascular treatment. Together, these results provide a deeper understanding of the clinical potential of PGG as a non-surgical treatment of AAAs.

5.
J Orthop Trauma ; 37(8): 412-416, 2023 08 01.
Article in English | MEDLINE | ID: mdl-37012637

ABSTRACT

OBJECTIVES: To determine whether primary arthrodesis (PA) or open reduction and internal fixation (ORIF) results in better functional outcomes through patient-reported outcome measures (PROMs). Reoperation rates and surgical characteristics among the 2 groups are evaluated as well. DESIGN: A retrospective cohort study. SETTING: Level 1 trauma center. PATIENTS: Eighty-one patients treated using PA or ORIF for Lisfranc injuries between January 2010 and January 2019. MAIN OUTCOME MEASUREMENTS: PROMs were collected using the validated Foot and Ankle Ability Measure questionnaire. Follow-up ranged from 1 to 10 years posttreatment. RESULTS: Two hundred patients underwent ORIF, and 72 patients underwent PA. Eighty-one of 272 patients responded to the questionnaire. The Foot and Ankle Ability Measure revealed activities of daily living subscores for PA and ORIF of 69.78 ± 18.61 and 73.53 ± 25.60, respectively ( P = 0.48). The Sports subscores for PA (45.81 ± 24.65) and ORIF (56.54 ± 31.13) were not significantly different ( P = 0.11). Perceived levels of activities of daily living ( P = 0.32) and Sports ( P = 0.81) function, compared with preinjury levels, were also not significantly different between the 2 groups. Rates of reoperation were nearly identical for PA (28.1%) and ORIF (30.6%) ( P = 1.00). CONCLUSION: Our results suggest that neither PA nor ORIF is superior regarding functional outcomes or rates of reoperation in the surgical treatment of Lisfranc injuries when appropriately triaged by the treating surgeon. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Subject(s)
Fractures, Bone , Humans , Fractures, Bone/surgery , Retrospective Studies , Activities of Daily Living , Open Fracture Reduction/methods , Arthrodesis/methods , Fracture Fixation, Internal/methods , Treatment Outcome
6.
J Agric Food Chem ; 2023 Feb 13.
Article in English | MEDLINE | ID: mdl-36780332

ABSTRACT

Commonalities in adaptive responses to abiotic stressors could contribute to the development of cross-resistance in weeds. The degree to which herbicide-induced changes in weeds parallel those induced by other abiotic stress remains unknown. We investigated the specificity of metabolic perturbations induced by glyphosate and drought across three glyphosate-resistant (GR) and two glyphosate-susceptible (GS) biotypes of Palmer amaranth (Amaranthus palmeri) using global metabolomics approaches. Compared to GS-biotypes, in the absence of stress, the GR-biotypes had a higher abundance of primary metabolites, including sugars, nonaromatic amino acids, and organic acids. However, despite having a higher 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene copy number that could upregulate the phenylpropanoid metabolism, the nonstressed GR-biotypes were less abundant in specialized (secondary) metabolites. Under glyphosate stress, 80% of metabolites, including shikimate, that accumulated in GS-biotypes also increased in the GR-biotypes. However, glyphosate triggered the preferential accumulation of glycosides of dihydroxylated and methoxylated flavanols with higher antioxidant potential, and ferulic acid derivatives, specifically in GR-biotypes. The disruption of the shikimate pathway and the accumulation of phenylpropanoids upon glyphosate exposure suggest that the stress response of GR-biotypes could be partly induced. This differential response was less evident in other phytochemical classes and under drought, highlighting that the phytochemical responses are stress-specific rather than biotype-specific.

7.
BMC Public Health ; 22(1): 1224, 2022 06 20.
Article in English | MEDLINE | ID: mdl-35725421

ABSTRACT

BACKGROUND: Maternal knowledge that motivates improvements in critical perinatal health behaviors has the potential to significantly reduce maternal and neonatal mortality. However, evidence-based health information often fails to reach mothers and their partners. mHealth video micro-messages, which disseminate evidence-based perinatal health messages, have the potential to address this gap. METHODS: The study will make use of a mixed method design, using both qualitative and quantitative methods. The study consists of two phases. During Phase 1, qualitative in-depth interviews will be used as part of a human-centered design approach to co-create 10 videos on priority perinatal behaviors. During Phase 2, quantitative methods (a randomized control trial) will be used to test the effectiveness of the videos in improving maternal knowledge and intended behavioral change. DISCUSSION: We hypothesize that by engaging mothers and their partners through emotive, resonant narratives and visuals, we can facilitate the delivery of evidence-based health messages at the foundation of perinatal health, thereby motivating life-saving improvements in health behaviors during the perinatal period. TRIAL REGISTRATION: This trial has been prospectively registered on the Pan African Clinical Trials Registry (PACTR), with the registration number PACTR202203673222680 . Registration date: 14 March 2022.  TRIAL REGISTRATION WHO DATA SET: Registry - Pan African Clinical Trials Registry (PACTR). Date: 14 March 2022. Secondary identification number - grant number: GCCSOAFMNH1. Source of support: Science for Africa Foundation. Primary sponsor - Clinton Health Access Initiative South Africa. Secondary sponsor - Stanford University School of Medicine and Heidelberg University. Contact for public & scientific queries: amandlamamasa@clintonhealthaccess.org ; +27 123,426,911; 1166 Francis Baard St, Hatfield, Pretoria, 0028. Public title - Amandla Mama. Scientific title - Optimizing knowledge and behavioral intention of women and their partners in the perinatal period in South Africa. Countries of recruitment - South Africa. Health conditions - antenatal care. Intervention - Amandla Mama mHealth videos, short 2D animated health promotional videos that promote healthy behavior in expectant mothers. Inclusion and exclusion criteria - Expectant mothers and their partners must be 18 years and older. Study type - randomized control trial. Date of first enrollment - 14 March 2021. Sample size - plan to enrol 450 participants, participants enrolled 29 participants. Recruitment Status - suspended. Primary outcome - improving knowledge. Secondary outcome - intended behavioral change. Ethics review - Approved on 24 January 2022 by Pharma-Ethics, contact Mrs. Marzelle Haskins, marzelle@pharma-ethics.co.za . Completion date - N/A. Summary results - N/A. IPD sharing statement - yes, through the publication of results in a journal article.


Subject(s)
Intention , Parturition , Clinical Trials, Phase II as Topic , Female , Health Behavior , Humans , Infant, Newborn , Mothers , Pregnancy , Randomized Controlled Trials as Topic , South Africa
8.
J Perinat Educ ; 31(2): 66-70, 2022 Apr 01.
Article in English | MEDLINE | ID: mdl-35386490

ABSTRACT

The author shares her story of moving beyond fear of childbirth, preparing for the birth of her baby, and the profound experience of giving birth. She shares the details of her preparation and education from childbirth classes, and the support she received from her nurse (her angel) and her husband (her steadfast star). It is a story of overcoming fear, working intensely during labor, leaning on a chosen support team and savoring the joy of finally giving birth to her son.

10.
Evolution ; 76(3): 512-527, 2022 03.
Article in English | MEDLINE | ID: mdl-35038345

ABSTRACT

Phenotypic plasticity is predicted to evolve in environmentally variable habitats, or those experiencing a high frequency of strong selection. The evolution of plasticity may however be constrained by costs or physiological limitations. In flowers, UV-absorbing pigmentation ameliorates UV damage to pollen, and is linked with elevated UV exposure. Whether plasticity contributes to this pattern remains unclear. Petals of Argentina anserina have larger UV-absorbing petal areas at high elevations where they experience higher and more variable UV exposure than low elevations. We measured UV-induced pigmentation plasticity in high- and low-elevation populations (hereafter, "high," "low"), and selection on pigmentation via male fitness. We dissected UV pigment biochemistry using metabolomics to explore biochemical mechanisms underlying plasticity. High displayed positive UV-induced pigmentation plasticity but low lacked plasticity. Selection favored elevated pigmentation under UV in high, supporting adaptive plasticity. In high, UV absorption was conferred by flavonoids produced in one flavonoid pathway branch. However, in low, UV absorption was associated with many compounds spanning multiple branches. Elevated plasticity was thus associated with reduced pigment diversity. These results are consistent with adaptive floral pigmentation plasticity in more extreme and variable environments. We discuss how biochemical underpinnings of pigmentation may permit or constrain the evolution of pigmentation plasticity.


Subject(s)
Flowers , Pigmentation , Adaptation, Physiological , Flavonoids/metabolism , Flowers/physiology , Pigmentation/physiology , Pollen
11.
Sci Rep ; 11(1): 21570, 2021 11 03.
Article in English | MEDLINE | ID: mdl-34732779

ABSTRACT

Plant uptake and metabolism of pesticides are complex and dynamic processes, which contribute to the overall toxicity of the pesticides. We investigated the metabolic fate of cyantraniliprole, a new diamide class of insecticide, during various growth stages of tomato. Cyantraniliprole was the major residue in leaves, flowers, and fruits, with the relative metabolite-to-parent ratios maintained at < 10% up to 28 days after treatment (DAT). Mature leaves contained consistently higher residues of cyantraniliprole than young leaves throughout the study. Flowers contained the highest cyantraniliprole residues up to 21 DAT, then gradually decreased. Immature green fruits had the highest cyantraniliprole residues (5.3 ± 0.7 ng/g; 42 DAT), and decreased toward red ripening stages (1.4 ± 0.2 ng/g; 84 DAT). Metabolism of cyantraniliprole primarily occurred in the foliage, where 21 metabolites were tentatively identified. Flowers and fruits contained 14 and four of these metabolites, respectively. Major transformation pathways were characterized by ring closure, followed by N-demethylation, and glycosylation. Additionally, plant metabolism of cyantraniliprole was also associated with several minor phase-I, phase-II, and breakdown metabolites. The occurrence of these metabolites in plants varied as a function of tissue types and their developmental stages. Our study highlights a tissue-specific biotransformation and accumulation of metabolites of cyantraniliprole in tomato.


Subject(s)
Diamide/analysis , Insecticides/analysis , Pyrazoles/analysis , Solanum lycopersicum/drug effects , ortho-Aminobenzoates/analysis , Limit of Detection , Mass Spectrometry , Metabolomics , Pesticide Residues/analysis , Pesticides/metabolism , Plant Leaves/drug effects
12.
Chemosphere ; 281: 130753, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34015651

ABSTRACT

Dissipation and transformation of cyantraniliprole, a new diamide class of insecticides, were investigated under greenhouse conditions, using snapdragon (Antirrhinum majus) as the model plant. Dissipation of cyantraniliprole in treated leaves was found to be dependent upon application methods (foliar spray versus soil drench) and doses (high versus low dose), with the parent insecticide being the major residue at various sampling points. A high-dose foliar application resulted in pesticide residue of 6.7-23.8 µg/g foliar fresh weight over 8 weeks of treatments, while in soil drench treatment the residue varied from 0.8 to 1.4 µg/g. However, the residue contents were similar between the two application methods at a low application dose. The transformation pathways of cyantraniliprole were primarily intramolecular rearrangements, with IN-J9Z38 being the major metabolite across treatments. Several other metabolites were also identified, some of which were unique to the application methods. Out of total 26 metabolites tentatively identified in this study, 10 metabolites were unique to foliar application, while six metabolites were unique to soil drench. In addition to plant-mediated biotransformation, photodegradation of the parent compound was identified as a potential mechanism in foliar application.


Subject(s)
Antirrhinum , Insecticides , Pesticide Residues , Diamide , Insecticides/analysis , Pesticide Residues/analysis , Pyrazoles , ortho-Aminobenzoates/analysis
13.
BMJ Glob Health ; 6(2)2021 02.
Article in English | MEDLINE | ID: mdl-33627361

ABSTRACT

On 5 March 2020, South Africa recorded its first case of imported COVID-19. Since then, cases in South Africa have increased exponentially with significant community transmission. A multisectoral approach to containing and mitigating the spread of SARS-CoV-2 was instituted, led by the South African National Department of Health. A National COVID-19 Command Council was established to take government-wide decisions. An adapted World Health Organiszion (WHO) COVID-19 strategy for containing and mitigating the spread of the virus was implemented by the National Department of Health. The strategy included the creation of national and provincial incident management teams (IMTs), which comprised of a variety of work streams, namely, governance and leadership; medical supplies; port and environmental health; epidemiology and response; facility readiness and case management; emergency medical services; information systems; risk communication and community engagement; occupational health and safety and human resources. The following were the most salient lessons learnt between March and September 2020: strengthened command and control were achieved through both centralised and decentralised IMTs; swift evidenced-based decision-making from the highest political levels for instituting lockdowns to buy time to prepare the health system; the stringent lockdown enabled the health sector to increase its healthcare capacity. Despite these successes, the stringent lockdown measures resulted in economic hardship particularly for the most vulnerable sections of the population.


Subject(s)
COVID-19/epidemiology , COVID-19/prevention & control , Communicable Disease Control/organization & administration , Pandemics , Contact Tracing , Humans , Incidence , Mass Screening , SARS-CoV-2 , South Africa/epidemiology
14.
Eval Program Plann ; 82: 101832, 2020 10.
Article in English | MEDLINE | ID: mdl-32585317

ABSTRACT

The unsuccessful implementation of health innovations occurs frequently, leading to missed opportunities where improvements could have been made on various aspects of a health system. The purpose of this study is to identify, assess and synthesise the facilitators and barriers to sustainably implementing evidence-based health innovations in a low- and middle-income country (LMIC) context. To identify the LMIC specific facilitators and barriers, a systematic literature review was conducted. 79 studies were analysed, and the implementation barriers and facilitators identified in each study were extracted. The extracted barriers and facilitators were categorised and synthesized into one of seven concepts: context, innovation, relations and networks, institutions, knowledge, actors or resources. There were no substantial variations between the frequency that each concept was identified as a facilitator or barrier to implementation. However, resources, which includes time, human, financial and physical resources, was the most frequently mentioned concept; emphasising the need to focus on the resource situation in LMICs. This study contributes to the growing literature that aims to inform health system planners and evaluators in LMICs on effectively and sustainably implementing evidence-based health innovations.


Subject(s)
Developing Countries , Poverty , Humans , Income , Program Evaluation
15.
Plant Cell Physiol ; 61(6): 1028-1040, 2020 Jun 01.
Article in English | MEDLINE | ID: mdl-32311031

ABSTRACT

Cellular homeostasis is maintained by the proteasomal degradation of regulatory and misfolded proteins, which sustains the amino acid pool. Although proteasomes alleviate stress by removing damaged proteins, mounting evidence indicates that severe stress caused by salt, metal(oids), and some pathogens can impair the proteasome. However, the consequences of proteasome inhibition in plants are not well understood and even less is known about how its malfunctioning alters metabolic activities. Lethality causes by proteasome inhibition in non-photosynthetic organisms stem from amino acid depletion, and we hypothesized that plants respond to proteasome inhibition by increasing amino acid biosynthesis. To address these questions, the short-term effects of proteasome inhibition were monitored for 3, 8 and 48 h in the roots of Brassica napus treated with the proteasome inhibitor MG132. Proteasome inhibition did not affect the pool of free amino acids after 48 h, which was attributed to elevated de novo amino acid synthesis; these observations coincided with increased levels of sulfite reductase and nitrate reductase activities at earlier time points. However, elevated amino acid synthesis failed to fully restore protein synthesis. In addition, transcriptome analysis points to perturbed abscisic acid signaling and decreased sugar metabolism after 8 h of proteasome inhibition. Proteasome inhibition increased the levels of alternative oxidase but decreased aconitase activity, most sugars and tricarboxylic acid metabolites in root tissue after 48 h. These metabolic responses occurred before we observed an accumulation of reactive oxygen species. We discuss how the metabolic response to proteasome inhibition and abiotic stress partially overlap in plants.


Subject(s)
Amino Acids/biosynthesis , Brassica napus/metabolism , Plant Roots/metabolism , Proteasome Endopeptidase Complex/metabolism , Proteolysis , Adenosine Triphosphate/metabolism , Brassica napus/drug effects , Brassica napus/growth & development , Cell Respiration , Dimethyl Sulfoxide/pharmacology , Glutamate-Ammonia Ligase/metabolism , Oxygen Consumption , Plant Proteins/metabolism , Proteasome Endopeptidase Complex/drug effects , Reactive Oxygen Species/metabolism , Stress, Physiological
16.
Am Fam Physician ; 100(1): 16-17, 2019 Jul 01.
Article in English | MEDLINE | ID: mdl-31259496
17.
Mol Pharmacol ; 95(5): 528-536, 2019 05.
Article in English | MEDLINE | ID: mdl-30858165

ABSTRACT

Head and neck squamous cell carcinoma (HNSCC) is a common and debilitating form of cancer characterized by poor patient outcomes and low survival rates. In HNSCC, genetic aberrations in phosphatidylinositol 3-kinase (PI3K) and epidermal growth factor receptor (EGFR) pathway genes are common, and small molecules targeting these pathways have shown modest effects as monotherapies in patients. Whereas emerging preclinical data support the combined use of PI3K and EGFR inhibitors in HNSCC, in-human studies have displayed limited clinical success so far. Here, we examined the responses of a large panel of patient-derived HNSCC cell lines to various combinations of PI3K and EGFR inhibitors, including EGFR agents with varying specificity and mechanistic characteristics. We confirmed the efficacy of PI3K and EGFR combination therapies, observing synergy with α isoform-selective PI3K inhibitor HS-173 and irreversible EGFR/ERBB2 dual inhibitor afatinib in most models tested. Surprisingly, however, our results demonstrated only modest improvement in response to HS-173 with reversible EGFR inhibitor gefitinib. This difference in efficacy was not explained by differences in ERBB target selectivity between afatinib and gefitinib; despite effectively disrupting ERBB2 phosphorylation, the addition of ERBB2 inhibitor CP-724714 failed to enhance the effect of HS-173 gefitinib dual therapy. Accordingly, although irreversible ERBB inhibitors showed strong synergistic activity with HS-173 in our models, none of the reversible ERBB inhibitors were synergistic in our study. Therefore, our results suggest that the ERBB inhibitor mechanism of action may be critical for enhanced synergy with PI3K inhibitors in HNSCC patients and motivate further preclinical studies for ERBB and PI3K combination therapies.


Subject(s)
Head and Neck Neoplasms/drug therapy , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Squamous Cell Carcinoma of Head and Neck/drug therapy , Afatinib/pharmacology , Cell Line, Tumor , Enzyme Inhibitors/pharmacology , ErbB Receptors/antagonists & inhibitors , Gefitinib/pharmacology , Head and Neck Neoplasms/metabolism , Humans , Pyridines/pharmacology , Quinazolines/pharmacology , Receptor, ErbB-2/metabolism , Signal Transduction/drug effects , Squamous Cell Carcinoma of Head and Neck/metabolism , Sulfonamides/pharmacology
18.
J Pediatr ; 198: 104-109, 2018 07.
Article in English | MEDLINE | ID: mdl-29631768

ABSTRACT

OBJECTIVES: To estimate the prevalence of childhood permanent hearing loss (PHL) after early cardiac surgery. STUDY DESIGN: This prospective observational (1996-2015) study after complex cardiac surgery with cardiopulmonary bypass at ≤6 weeks of life reports audiology follow-up by registered pediatric-experienced audiologists at 6-8 months postsurgery, age 2 years, and as required throughout and thereafter to complete diagnoses. PHL at any frequency (500-4000 Hz) is defined as responses of >25-decibel hearing level in either ear. PHL was evaluated by type (conductive or sensorineural), pattern (flat or sloping), and severity (mild to profound). RESULTS: Survival rate was 83.4% (706 of 841 children) with a 97.9% follow-up rate (691 children); 41 children had PHL, 5.9% (95% CI 4.3%, 8.0%). By cardiac defect, prevalence was biventricular, 4.0% (95%CI 2.5%, 6.1%); single ventricle, 10.8% (95%CI 6.8%, 16.1%). Eighty-seven (12.6%) of 691 had syndromes/genetic abnormalities with known association with PHL; of these, 17 (41.5%) had PHL. Of 41 children, 4 had permanent conductive, moderate to severe loss (1 bilateral); 37 had moderate to profound sensorineural loss (29 bilateral with 20 sloping and 9 flat), 6 with cochlear implant done or recommended. CONCLUSIONS: Infants surviving complex cardiac surgery are at high risk for PHL. Over 40% with PHL have known syndromes/genetic abnormalities, but others do not have easily identifiable risk indicators. Early cardiac surgery should be considered a risk indicator for PHL.


Subject(s)
Cardiac Surgical Procedures , Cardiopulmonary Bypass , Hearing Loss/diagnosis , Hearing Loss/epidemiology , Heart Defects, Congenital/surgery , Age Factors , Child, Preschool , Female , Heart Defects, Congenital/complications , Heart Defects, Congenital/mortality , Humans , Infant , Infant, Newborn , Male , Prevalence , Prospective Studies , Risk Factors
19.
Prev Chronic Dis ; 15: E33, 2018 03 15.
Article in English | MEDLINE | ID: mdl-29543584

ABSTRACT

INTRODUCTION: Approximately 60% of the American diet comes from processed foods, which makes improving their nutritional quality important for Americans' health. The objective of this study was to measure changes in serving sizes, calories, and sodium in top-selling processed foods that were on the market in 2009 and 2015. METHODS: We analyzed products in the top 80% of sales in the 54 processed food categories with consistent serving sizes and sales metrics that were on the market in both 2009 and 2015. Mean serving size, calories (per serving and density), sodium (per serving and density), and sales were calculated for 2,979 branded processed food products. For each stratification of calorie density and sodium density (decreased, increased, or did not change), we calculated the mean serving size, calorie density, sodium density, and sales for each year. RESULTS: From 2009 to 2015, we found decreases in serving size (-2.3%, P < .001), calories per serving (-2.0%, P < .001), calorie density (-1.1%, P < .001), sodium per serving (-7.6%, P < .001), and sodium density (-6.0%, P < .001). A decrease in calorie density did not correspond to an increase in sodium density or vice versa. A decline in sales was observed regardless of whether calorie density or sodium density decreased, increased, or did not change. CONCLUSION: Reductions in calorie and sodium density occurred in tandem, suggesting that manufacturers reformulated for more than one health goal at the same time. Instead of unintended negative consequences of encouraging companies to reformulate for one nutrient, an overall net nutritional benefit occurred.


Subject(s)
Energy Intake , Food/classification , Serving Size/trends , Sodium, Dietary , Chronic Disease/prevention & control , Databases, Factual , Feeding Behavior , Food/adverse effects , Humans , Serving Size/statistics & numerical data , United States
20.
Prim Care ; 45(1): 131-141, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29406939

ABSTRACT

Cardiovascular disease in women as a distinct disease entity is underappreciated relative to other female-specific diseases. A perception that cardiovascular disease affects men more commonly and a lack of understanding about the underlying pathophysiology of cardiovascular disease in women contribute to this phenomenon. Hormonal changes, pregnancy-related conditions, and cancer therapies have an impact on endothelial function, vascular anatomy, and myocardial contractility. Women with heart disease often present later, receive care not consistent with accepted guidelines, and have less access to diagnostic and therapeutic resources. Understanding the differences and challenges of treating cardiovascular disease in women is essential to improving population health.


Subject(s)
Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/therapy , Female , Humans , Risk Factors , Sex Factors
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