Search

Importance: Meniere disease accounts for up to 15% of new vestibular diagnoses,; however, the optimal treatment has yet to be identified. A conservative treatment that would reduce or stop the vertigo episodes has not been identified., Objective: To determine the efficacy of a serotonin-norepinephrine reuptake inhibitor, venlafaxine, compared to placebo in treating patients with Meniere disease., Design, Setting, and Participants: This was a randomized, double-blind, placebo-controlled, crossover pilot study spanning 22 weeks of follow-up. The clinical trial took place at a single-center tertiary referral center in Charleston, South Carolina. Participants were eligible if they were 18 years or older, had definite Meniere disease criteria as defined by Barany criteria, had at least 2 episodes in the last month, had not received intratympanic gentamycin, skull base surgery, or radiation therapy to the head or neck, not currently taking diuretics for Meniere disease, not currently taking oral steroids, and not currently taking serotonin-modulating medication. Patients were enrolled between February 2020 and September 2023., Interventions: Patients received either 1 venlafaxine tablet, 37.5 mg, taken daily by mouth for 8 weeks or 1 placebo tablet taken daily by mouth for 8 weeks. Group 1 received placebo during phase 1 of the trial and venlafaxine in phase 2 of the trial. Group 2 received venlafaxine during phase 1 of the trial and placebo in phase 2 of the trial., Main Outcomes and Measures: The main outcomes included the number of episodes and scores on the following scales: Dizziness Handicap Inventory, Neuropsychological Vertigo Inventory, Meniere Disease Patient-Oriented Symptom Index, 20-Item Short Form Health Survey, Penn State Worry Questionnaire, Cognitive Failure Questionnaire., Results: A total of 182 patients were screened, and 40 participants with Meniere disease enrolled in the trial. The mean (SD) age of participants was 56.6 (14.3) years, and 22 (55%) were female. Participants had a mean (SD) of 13.8 (10.1) episodes per phase at baseline, 5.4 (4.4) episodes (Δ8.4) during the venlafaxine phase, and 5.0 (4.6) episodes (Δ8.8) during the placebo phase. No significant difference was identified between venlafaxine and placebo groups in the number of episodes or quality-of-life metrics., Conclusions and Relevance: This randomized clinical trial failed to identify a difference between venlafaxine and placebo in number of episodes and other quality-of-life metrics. Future studies may benefit from different dosing regimens, larger cohorts, and longer lengths of therapy., Trial Registration: ClinicalTrials.gov Identifier: NCT04218123.

Introduction: While the presence of human papillomavirus (HPV) is known to affect the outcomes of oropharyngeal squamous cell carcinoma (OPSCC), there is a significant gap in research regarding the potential sex-based differences. This systematic review-metanalysis (SR-MA) aims to evaluate if sex is a prognostic factor in HPV-associated OPSCC., Methods: A systematic review and meta-analysis was performed. COCHRANE Library, CINAHL, PubMed, and Scopus were searched for English-language articles from 1966 to October 2023. Studies with multivariable analysis of overall survival (OS) based on sex were included. Adjusted hazard ratios (aHRs) with a 95 % confidence interval (CI) were presented for the reported outcome. A meta-analysis of single means, proportions, and aHRs with a 95 % CI was conducted., Results: This SR-MA included 24 studies (n = 101,574). The proportion of female patients was 16.6 % [15.4 %-17.8 %]. A meta-analysis of all included studies with OS showed no significant difference in survival between male and female patients. In US-based studies, no significant difference in OS is observed between male and female patients. International studies reported a better OS for female patients (aHR = 0.68, 95 % CI, 0.48-0.95)., Conclusion: This meta-analysis suggests that sex does not represent a significant prognostic factor for patients affected by HPV associated OPSCC. When stratified by geographic location, findings suggests that female patients from the US with HPV OPSCC have similar OS than male patients but in international studies it suggests male patients have worse OS., (Copyright © 2024. Published by Elsevier Inc.)

This article seeks to evaluate the scientific landscape of the phytoremediation of mine tailings through a series of bibliometric and scientometric techniques. Phytoremediation has emerged as a sustainable approach to remediate metal-contaminated mine waste areas. A scientometric analysis of 913 publications indexed in Web of Science from 1999 to 2023 was conducted using CiteSpace. The results reveal an expanding, interdisciplinary field with environmental sciences as the core category. Keyword analysis of 561 nodes and 2,825 links shows a focus on plant-metal interactions, microbial partnerships, bioavailability, and field validation. Co-citation analysis of 1,032 nodes and 2,944 links identifies seminal works on native species, plant-microbe interactions, and amendments. Temporal mapping of 15 co-citation clusters indicates a progression from early risk assessments and native plant inquiries to integrated biological systems, economic feasibility, and sustainability considerations. Recent trends emphasize multidimensional factors influencing adoption, such as plant-soil-microbe interactions, organic amendments, and field-scale performance evaluation. The findings demonstrate an intensifying translation of phytoremediation from scientific novelty to engineering practice. This quantitative and qualitative analysis of research trends aids in understanding the development of phytoremediation for mine tailings. The results provide valuable insights for researchers and practitioners in this evolving field.

Clear cell renal cell carcinoma (ccRCC) incidence has risen steadily over the last decade. Elevated lipid uptake and storage is required for ccRCC cell viability. As stored cholesterol is the most abundant component in ccRCC intracellular lipid droplets, it may also play an important role in ccRCC cellular homeostasis. In support of this hypothesis, ccRCC cells acquire exogenous cholesterol through the high-density lipoprotein receptor SCARB1, inhibition or suppression of which induces apoptosis. Here, we showed that elevated expression of 3 beta-hydroxy steroid dehydrogenase type 7 (HSD3B7), which metabolizes cholesterol-derived oxysterols in the bile acid biosynthetic pathway, is also essential for ccRCC cell survival. Development of an HSD3B7 enzymatic assay and screening for small-molecule inhibitors uncovered the compound celastrol as a potent HSD3B7 inhibitor with low micromolar activity. Repressing HSD3B7 expression genetically or treating ccRCC cells with celastrol resulted in toxic oxysterol accumulation, impaired proliferation, and increased apoptosis in vitro and in vivo. These data demonstrate that bile acid synthesis regulates cholesterol homeostasis in ccRCC and identifies HSD3B7 as a plausible therapeutic target., Significance: The bile acid biosynthetic enzyme HSD3B7 is essential for ccRCC cell survival and can be targeted to induce accumulation of cholesterol-derived oxysterols and apoptotic cell death., (©2024 American Association for Cancer Research.)

Availability of the essential amino acid methionine affects cellular metabolism and growth, and dietary methionine restriction has been implicated as a cancer therapeutic strategy. Nevertheless, how liver cancer cells respond to methionine deprivation and underlying mechanisms remain unclear. Here we find that human liver cancer cells undergo irreversible cell cycle arrest upon methionine deprivation in vitro. Blocking methionine adenosyl transferase 2A (MAT2A)-dependent methionine catabolism induces cell cycle arrest and DNA damage in liver cancer cells, resulting in cellular senescence. A pharmacological screen further identified GSK3 inhibitors as senolytics that selectively kill MAT2A-inhibited senescent liver cancer cells. Importantly, combined treatment with MAT2A and GSK3 inhibitors therapeutically blunts liver tumor growth in vitro and in vivo across multiple models. Together, methionine catabolism is essential for liver tumor growth, and its inhibition can be exploited as an improved pro-senescence strategy for combination with senolytic agents to treat liver cancer., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Many vegetal species can accumulate great amounts of metallic elements in their tissues. For this reason, they are called metal hyperaccumulators. An indicator of great interest in environmental sciences is the bioconcentration factor because it is recognized for establishing the potential accumulation of chemicals in organisms. Particularly in soil phytoremediation processes, it measures the capacity of a certain plant to capture metals, in terms of soil concentration. According to their behavior, four types of plants can be distinguished regarding soil concentration increase: indicator, excluder, accumulator, and hyperaccumulator. This study proposes a new model to categorize plants according to their behavior related to soil concentration increase, using several characteristic curves obtained from 1288 experimental measurements collected from different bibliographic sources. The metals analyzed were Cu, Fe, Pb, and Zn. The proposed model is obtained through linear regression and nonlinear transformations to model the expected behavior of plants in high concentration conditions. In particular, the basic equation of the model has three key components to represent the expected concentration in the plant root given the final soil concentration level, the type of species, and specific metal: a linear factor that determines the growth for low concentration values, an exponential factor that determines its decrease for high concentration values, and a logarithmic factor that limits the maximum value that can be reached in practice and influences the decay for high concentration values. After fitting the experimental data using linear regression, the proposed model has a 0.084 R 2 determination coefficient and all of its parameters are considered significant. Furthermore, it shows that 60 of the 257 species assessed behave as accumulators and 10 of them as hyperaccumulators. The main contribution of this model is its ability to handle soils with high concentrations, where it would be hard for plants to achieve concentrations similar to or higher than the substrate containing them. Thus, the conventional criterion of the bioconcentration factor would incorrectly categorize a plant as an excluder. In contrast, this new model allows assessing plant effectiveness in a phytoremediation process of highly concentrated affected sites, such as mine tailings., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

This article proposes a mathematical model to characterize phytoremediation processes in soils contaminated with heavy metals. In particular, the proposed model constructs characteristic curves for the concentrations of several metals (As, Cd, Cu, Fe, Pb, Sb, and Zn) in soils and plants based on the experimental data retrieved from several bibliographical sources comprising 305 vegetal species. The proposed model is an extension of previous models of characteristic curves in phytoremediation processes developed by Lam et al. for root measurements using the bioconcentration factor. However, the proposed model extends this approach to consider roots, as well as aerial parts and shoots of the plant, while at the same time providing a less complex mathematical formula compared to the original. The final model shows an adjusted R2 of 0.712, and all its parameters are considered statistically significant. The model may be used to assess samples from a given plant species to identify its potential as an accumulator in the context of soil phytoremediation processes. Furthermore, a simplified version of the model was constructed using an approximation to provide an easy-to-compute alternative that is valid for concentrations below 37,000 mg/kg. This simplified model shows results similar to the original model for concentrations below this threshold and it uses an adjusted factor defined as [Formula: see text] that must be compared with a threshold depending on the metal, type of measurement, and target (e.g., accumulator or hyperaccumulator). The full model construction shows that 90 out of the 305 species assessed have a potential behavior as accumulators and 10 of them as hyperaccumulators. Finally, out of the 1405 experimental measurements, 1177 were shown to be accumulators or hyperaccumulators. In particular, 85% of the results coincide with the reported values, thus validating the proposed model., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Polyunsaturated fatty acids (PUFA) and highly unsaturated fatty acid (HUFA) synthetic products and their signaling metabolites play vital roles in immunity, inflammation, and brain development/function. Frequency differences of variants within the fatty acid desaturase ( FADS ) gene cluster affect levels of HUFAs, their biologically active products, and numerous physiological phenotypes. Fundamental questions remain regarding the impact of this genetic variation on the health of Hispanic/Latino populations., Methods: Data and biospecimens (plasma, red blood cells, buffy coat-derived DNA) from 135 participants (83.7% female) were used to assess the relationship(s) between dietary PUFA levels, a FADS haplotype tagging SNP, rs174537, and the capacity of Hispanic/Latino populations to generate HUFAs in plasma and RBC as well as its potential impact on anthropomorphic phenotypes., Results: The dietary habits of the cohort showed that participant diets contained a high ratio (9.3 ± 0.2, mean ± SEM) of linoleic acid ( n -6) to alpha-linolenic acid ( n -3) and also contained extremely low levels of n -3 HUFAs (eicosapentaenoic acid, EPA and docosahexaenoic acid, DHA), both features of the Modern Western Diet. Compared to African and European American cohorts, the frequency of the TT rs174537 genotype was highly enriched (53% of subjects) in this Hispanic/Latino cohort and was strongly associated with lower circulating HUFA levels. For example, plasma levels of arachidonic acid (ARA: 20:4, n -6) and EPA (20:5, n -3) were 37% and 23%, respectively, lower in the TT versus the GG genotype. HUFA biosynthetic efficiency, as determined by metabolic product to precursor ratios, was highly dependent ( p  < 0.0001) on the rs174537 genotype (GG > GT > TT) for both circulating n -6 and n -3 HUFAs. In contrast, the RBC Omega-3 Index (EPA + DHA) was extremely low (2.89 ± 1.65, mean ± sd) in this population and independent of rs174537 genotype. Importantly, the rs174537 genotype was also related to female height with TT genotype participants being 4.5 cm shorter ( p  = 0.0001) than the GG + GT participants., Discussion: Taken together, this study illustrates that dietary PUFA + HUFA ×  FADS gene- interactions place a large proportion (>50%) of Hispanic/Latino populations at high risk of a deficiency in both circulating and cellular levels of n -3 HUFAs., Competing Interests: FC is a co-founder of a start-up company TyrianOmega, which focuses on the production of omega-3 PUFAs by cyanobacteria, largely for animal feeds and aquaculture. He is also the co-founder of Resonance Pharma, which focuses on determining clinical level of and inhibitors that block secreted phospholipase A2 isoforms. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sergeant, Keith, Seeds, Legins, Young, Vitolins and Chilton.)

Objectives: We aim to establish daily risk estimates of the relationships between grass, tree and weed pollen and asthma health outcomes., Design: Time series regression analysis of exposure and health outcomes using interaction by month to determine risk estimates all year round., Setting: Metropolitan Adelaide, South Australia., Participants: Health outcomes for asthma are based on 15 years of hospital admissions, 13 years emergency presentations and ambulance callouts. In adults (≥18 years), there were 10 381 hospitalisations, 26 098 emergency department (ED) presentations and 11 799 ambulance callouts and in children (0-17 years), 22 114, 39 813 and 3774, respectively., Outcome Measures: The cumulative effect of 7 day lags was calculated as the sum of the coefficients and reported as incidence rate ratio (IRR) related to an increase in 10 grains of pollen/m 3 ., Results: In relation to grass pollen, children and adults were disparate in their timing of health effects. Asthma outcomes in children were positively related to grass pollen in May, and for adults in October. Positive associations with weed pollen in children was seen from February to May across all health outcomes. For adults, weed pollen-related health outcomes were restricted to February. Adults were not affected by tree pollen, while children's asthma morbidity was associated with tree pollen in August and September. In children, IRRs ranged from 1.14 (95% CI 1.06 to 1.21) for ED presentations for tree pollen in August to 1.98 (95% CI 1.06 to 3.72) for weed pollen in February. In adults, IRRs ranged from 1.28 (95% CI 1.01 to 1.62) for weed pollen in February to 1.31 (95% CI 1.08 to 1.57) for grass pollen in October., Conclusion: Monthly risk assessment indicated that most pollen-related asthma health outcomes in children occur in the colder part of the year, while adults are affected in the warm season. The findings indicate a need for year-round pollen monitoring and related health campaigns to provide effective public health prevention., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Kidney cancer is a common adult malignancy in the USA. Clear cell renal cell carcinoma (ccRCC), the predominant subtype of kidney cancer, is characterized by widespread metabolic changes. Urea metabolism is one such altered pathway in ccRCC. The aim of this study was to elucidate the contributions of urea cycle enzymes, argininosuccinate synthase 1 (ASS1), and argininosuccinate lyase (ASL) towards ccRCC progression., Methods: We employed a combination of computational, genetic, and metabolomic tools along with in vivo animal models to establish a tumor-suppressive role for ASS1 and ASL in ccRCC., Results: We show that the mRNA and protein expression of urea cycle enzymes ASS1 and ASL are reduced in ccRCC tumors when compared to the normal kidney. Furthermore, the loss of ASL in HK-2 cells (immortalized renal epithelial cells) promotes growth in 2D and 3D growth assays, while combined re-expression of ASS1 and ASL in ccRCC cell lines suppresses growth in 2D, 3D, and in vivo xenograft models. We establish that this suppression is dependent on their enzymatic activity. Finally, we demonstrate that conservation of cellular aspartate, regulation of nitric oxide synthesis, and pyrimidine production play pivotal roles in ASS1+ASL-mediated growth suppression in ccRCC., Conclusions: ccRCC tumors downregulate the components of the urea cycle including the enzymes argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL). These cytosolic enzymes lie at a critical metabolic hub in the cell and are involved in aspartate catabolism and arginine and nitric oxide biosynthesis. Loss of ASS1 and ASL helps cells redirect aspartate towards pyrimidine synthesis and support enhanced proliferation. Additionally, reduced levels of ASS1 and ASL might help regulate nitric oxide (NO) generation and mitigate its cytotoxic effects. Overall, our work adds to the understanding of urea cycle enzymes in a context-independent of ureagenesis, their role in ccRCC progression, and uncovers novel potential metabolic vulnerabilities in ccRCC., (© 2021. The Author(s).)

Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets containing free and esterified cholesterol; however, the functional significance of cholesterol accumulation in ccRCC cells is unknown. We demonstrate that, surprisingly, genes encoding cholesterol biosynthetic enzymes are repressed in ccRCC, suggesting a dependency on exogenous cholesterol. Mendelian randomization analyses based on 31,000 individuals indicate a causal link between elevated circulating high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import, and inhibiting SCARB1 is sufficient to cause ccRCC cell-cycle arrest, apoptosis, elevated intracellular reactive oxygen species levels, and decreased PI3K/AKT signaling. Collectively, we reveal a cholesterol dependency in ccRCC and implicate SCARB1 as a novel therapeutic target for treating kidney cancer., Significance: We demonstrate that ccRCC cells are auxotrophic for exogenous cholesterol to maintain PI3K/AKT signaling pathway and ROS homeostasis. Blocking cholesterol import through the HDL transporter SCARB1 compromises ccRCC cell survival and tumor growth, suggesting a novel pharmacologic target for this disease. This article is highlighted in the In This Issue feature, p. 2945., (©2021 American Association for Cancer Research.)

The crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, as well as the consequent effects on liver tumorigenesis, are not completely understood. We show here that hepatocyte-specific loss of the gluconeogenic enzyme fructose 1,6-bisphosphatase 1 (FBP1) disrupts liver metabolic homeostasis and promotes tumour progression. FBP1 is universally silenced in both human and murine liver tumours. Hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype. Depleting senescent HSCs by 'senolytic' treatment with dasatinib/quercetin or ABT-263 inhibits tumour progression. We further demonstrate that FBP1-deficient hepatocytes promote HSC activation by releasing HMGB1; blocking its release with the small molecule inflachromene limits FBP1-dependent HSC activation, the subsequent development of the senescence-associated secretory phenotype and tumour progression. Collectively, these findings provide genetic evidence for FBP1 as a metabolic tumour suppressor in liver cancer and establish a critical crosstalk between hepatocyte metabolism and HSC senescence that promotes tumour growth.

Myc activation is a primary oncogenic event in many human cancers; however, these transcription factors are difficult to inhibit pharmacologically, suggesting that Myc-dependent downstream effectors may be more tractable therapeutic targets. Here, we show that Myc overexpression induces endoplasmic reticulum (ER) stress and engages the inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 (XBP1) pathway through multiple molecular mechanisms in a variety of c-Myc- and N-Myc-dependent cancers. In particular, Myc-overexpressing cells require IRE1α/XBP1 signaling for sustained growth and survival in vitro and in vivo, dependent on elevated stearoyl-CoA-desaturase 1 (SCD1) activity. Pharmacological and genetic XBP1 inhibition induces Myc-dependent apoptosis, which is alleviated by exogenous unsaturated fatty acids. Of note, SCD1 inhibition phenocopies IRE1α RNase activity suppression in vivo. Furthermore, IRE1α inhibition enhances the cytotoxic effects of standard chemotherapy drugs used to treat c-Myc-overexpressing Burkitt's lymphoma, suggesting that inhibiting the IRE1α/XBP1 pathway is a useful general strategy for treatment of Myc-driven cancers.

von Hippel-Lindau (VHL) tumor suppressor loss results in hypoxia-inducible factor alpha (HIF-alpha) stabilization and occurs in 70% of sporadic clear cell renal carcinomas (ccRCCs). To determine whether opposing influences of HIF-1alpha and HIF-2alpha on c-Myc activity regulate human ccRCC progression, we analyzed VHL genotype and HIF-alpha expression in 160 primary tumors, which segregated into three groups with distinct molecular characteristics. Interestingly, ccRCCs with intact VHL, as well as pVHL-deficient HIF-1alpha/HIF-2alpha-expressing ccRCCs, exhibited enhanced Akt/mTOR and ERK/MAPK signaling. In contrast, pVHL-deficient ccRCCs expressing only HIF-2alpha displayed elevated c-Myc activity, resulting in enhanced proliferation and resistance to replication stress. These reproducible distinctions in ccRCC behavior delineate HIF-alpha effects on c-Myc in vivo and suggest molecular criteria for selecting targeted therapies.

The von Hippel-Lindau tumor suppressor pVHL regulates the stability of hypoxia-inducible factors (HIF)-1 and -2, oxygen-sensitive basic helix-loop-helix transcription factors, which mediate the hypoxic induction of angiogenic growth factors such as vascular endothelial growth factor. Loss of pVHL function results in constitutive activation of HIF-1 and HIF-2 and is associated with the development of highly vascularized tumors in multiple organs. We have used a conditional gene-targeting approach to investigate the relative contributions of HIF-1 and HIF-2 to VHL-associated vascular tumorigenesis in a mouse model of liver hemangiomas. Here we demonstrate genetically that conditional inactivation of HIF-2alpha suppressed the development of VHL-associated liver hemangiomas and that angiogenic gene expression in hepatocytes is predominantly regulated by HIF-2 and not by HIF-1. These findings suggest that HIF-2 is the dominant HIF in the pathogenesis of VHL-associated vascular tumors and that pharmacologic targeting of HIF-2 may be an effective strategy for their treatment.