Asunto(s)
Craneosinostosis , Enfermedades de los Perros , Exoftalmia , Intubación Intratraqueal , Perros , Animales , Intubación Intratraqueal/veterinaria , Intubación Intratraqueal/efectos adversos , Exoftalmia/veterinaria , Exoftalmia/etiología , Craneosinostosis/veterinaria , Masculino , FemeninoRESUMEN
The Mouse Metabolic Phenotyping Center (MMPC)Live Program was established in 2023 by the National Institute for Diabetes, Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH) to advance biomedical research by providing the scientific community with standardized, high quality phenotyping services for mouse models of diabetes and obesity. Emerging as the next iteration of the MMPC Program which served the biomedical research community for 20 years (2001-2021), MMPCLive is designed as an outwardly-facing consortium of service cores that collaborate to provide reduced-cost consultation and metabolic, physiologic, and behavioral phenotyping tests on live mice for U.S. biomedical researchers. Four MMPCLive Centers located at universities around the country perform complex and often unique procedures in vivo on a fee for service basis, typically on mice shipped from the client or directly from a repository or vendor. Current areas of expertise include energy balance and body composition, insulin action and secretion, whole body carbohydrate and lipid metabolism, cardiovascular and renal function, food intake and behavior, microbiome and xenometabolism, and metabolic pathway kinetics. Additionally, an opportunity arose to reduce barriers to access and expand the diversity of the biomedical research workforce by establishing the VIBRANT Program. Directed at researchers historically underrepresented in the biomedical sciences, VIBRANT-eligible investigators have access to testing services, travel and career development awards, expert advice and experimental design consultation, and short internships to learn test technologies. Data derived from experiments run by the Centers belongs to the researchers submitting mice for testing which can be made publicly available and accessible from the MMPCLive database following publication. In addition to services, MMPCLive staff provide expertise and advice to researchers, develop and refine test protocols, engage in outreach activities, publish scientific and technical papers, and conduct educational workshops and training sessions to aid researchers in unraveling the heterogeneity of diabetes and obesity.
RESUMEN
OBJECTIVE: To compare medication abortion (MAB) success in very early pregnancy (VEP) with mifepristone followed by either one or two doses of misoprostol. STUDY DESIGN: We performed a retrospective cohort analysis of VEP MABs from 7/1/2021 to 05/31/2022 treated with mifepristone 200mg oral followed by a single dose of misoprostol 800mcg buccal 24-48 hours later and MABs from 06/21/2022 to 10/31/2022 treated with mifepristone 200mg oral followed by two doses of misoprostol 800mcg buccal spaced four hours apart, with first dose taken 24-48 hours after mifepristone. Serum BhCG was collected at the time of mifepristone treatment with additional BhCG collected 48-72 hours after misoprostol treatment in both groups. Success was defined as a BhCG decline of > or = 50%. MAB failure was defined as ongoing, viable pregnancy determined by follow up ultrasound or procedural intervention with aspiration. RESULTS: There were 423 patients in the single dose misoprostol group and 262 patients in the two-dose misoprostol group. There were no significant differences between the two groups in baseline characteristics. In the single dose group, 372 (87.9%) were treated successfully; in the two-dose group, 224 (85.5%) were treated successfully. There was no significant difference in MAB success between the groups (p=0.73). CONCLUSION: The addition of a second dose of misoprostol does not improve the success of MAB in VEP. CLINICAL TRIAL REGISTRATION NUMBER: N/A.
RESUMEN
The kidneys facilitate energy conservation through reabsorption of nutrients including glucose. Almost all the filtered blood glucose is reabsorbed by the kidneys. Loss of glucose in urine (glycosuria) is offset by an increase in endogenous glucose production to maintain normal energy supply in the body. How the body senses this glucose loss and consequently enhances glucose production is unclear. Using renal Slc2a2 (also known as Glut2) knockout mice, we demonstrate that elevated glycosuria activates the hypothalamic-pituitary-adrenal axis, which in turn drives endogenous glucose production. This phenotype was attenuated by selective afferent renal denervation, indicating the involvement of the afferent nerves in promoting the compensatory increase in glucose production. In addition, through plasma proteomics analyses we observed that acute phase proteins - which are usually involved in the body's defense mechanisms against a threat - were the top candidates which were either upregulated or downregulated in renal Slc2a2 KO mice. Overall, afferent renal nerves contribute to promoting endogenous glucose production in response to elevated glycosuria and loss of glucose in urine is sensed as a biological threat in mice. These findings may be useful in improving the efficiency of drugs like SGLT2 inhibitors that are intended to treat hyperglycemia by enhancing glycosuria but are met with a compensatory increase in endogenous glucose production.
Asunto(s)
Transportador de Glucosa de Tipo 2 , Glucosa , Glucosuria , Hipotálamo , Riñón , Ratones Noqueados , Animales , Ratones , Glucosa/metabolismo , Riñón/metabolismo , Glucosuria/metabolismo , Transportador de Glucosa de Tipo 2/metabolismo , Transportador de Glucosa de Tipo 2/genética , Hipotálamo/metabolismo , Masculino , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiología , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/fisiologíaRESUMEN
Targeted alpha therapy (TAT) relies on chemical affinity or active targeting using radioimmunoconjugates as strategies to deliver α-emitting radionuclides to cancerous tissue. These strategies can be affected by transmetalation of the parent radionuclide by competing ions in vivo and the bond-breaking recoil energy of decay daughters. The retention of α-emitting radionuclides and the dose delivered to cancer cells are influenced by these processes. Encapsulating α-emitting radionuclides within nanoparticles can help overcome many of these challenges. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles are a biodegradable and biocompatible delivery platform that has been used for drug delivery. In this study, PLGA nanoparticles are utilized for encapsulation and retention of actinium-225 ([225Ac]Ac3+). Encapsulation of [225Ac]Ac3+ within PLGA nanoparticles (Zave = 155.3 nm) was achieved by adapting a double-emulsion solvent evaporation method. The encapsulation efficiency was affected by both the solvent conditions and the chelation of [225Ac]Ac3+. Chelation of [225Ac]Ac3+ to a lipophilic 2,9-bis-lactam-1,10-phenanthroline ligand ([225Ac]AcBLPhen) significantly decreased its release (< 2%) and that of its decay daughters (< 50%) from PLGA nanoparticles. PLGA nanoparticles encapsulating [225Ac]AcBLPhen significantly increased the delivery of [225Ac]Ac3+ to murine (E0771) and human (MCF-7 and MDA-MB-231) breast cancer cells with a concomitant increase in cell death over free [225Ac]Ac3+ in solution. These results demonstrate that PLGA nanoparticles have potential as radionuclide delivery platforms for TAT to advance precision radiotherapy for cancer. In addition, this technology offers an alternative use for ligands with poor aqueous solubility, low stability, or low affinity, allowing them to be repurposed for TAT by encapsulation within PLGA nanoparticles.
Asunto(s)
Actinio , Nanopartículas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Nanopartículas/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Actinio/química , Humanos , Línea Celular Tumoral , Animales , Partículas alfa/uso terapéutico , Ratones , Femenino , Materiales Biocompatibles/química , Neoplasias de la Mama/tratamiento farmacológico , Radioinmunoterapia/métodosRESUMEN
Clinical outcomes of arteriovenous fistulae (AVF) for hemodialysis remain inadequate since biological mechanisms of AVF maturation and failure are still poorly understood. Aortocaval fistula creation (AVF group) or a sham operation (sham group) was performed in C57BL/6 mice. Venous limbs were collected on postoperative day 7 and total RNA was extracted for high throughput RNA sequencing and bioinformatic analysis. Genes in metabolic pathways were significantly downregulated in the AVF, whereas significant sex differences were not detected. Since gene expression patterns among the AVF group were heterogenous, the AVF group was divided into a 'normal' AVF (nAVF) group and an 'outliers' (OUT) group. The gene expression patterns of the nAVF and OUT groups were consistent with previously published data showing venous adaptive remodeling, whereas enrichment analyses showed significant upregulation of metabolism, inflammation and coagulation in the OUT group compared to the nAVF group, suggesting the heterogeneity during venous remodeling reflects early gene expression changes that may correlate with AVF maturation or failure. Early detection of these processes may be a translational strategy to predict fistula failure and reduce patient morbidity.
Asunto(s)
Derivación Arteriovenosa Quirúrgica , Ratones Endogámicos C57BL , Remodelación Vascular , Animales , Ratones , Masculino , Remodelación Vascular/genética , Femenino , Regulación hacia Abajo/genética , Venas/metabolismo , Diálisis Renal , Fístula Arteriovenosa/genética , Fístula Arteriovenosa/metabolismo , Fístula Arteriovenosa/patología , Regulación de la Expresión Génica , Perfilación de la Expresión GénicaRESUMEN
OBJECTIVE: Obesity is associated with alterations in eating behavior and neurocognitive function. In this study, we investigate the effect of obesity on brain energy utilization, including brain glucose transport and metabolism. METHODS: A total of 11 lean participants and 7 young healthy participants with obesity (mean age, 27 years) underwent magnetic resonance spectroscopy scanning coupled with a hyperglycemic clamp (target, ~180 mg/dL) using [1-13C] glucose to measure brain glucose uptake and metabolism, as well as peripheral markers of insulin resistance. RESULTS: Individuals with obesity demonstrated an ~20% lower ratio of brain glucose uptake to cerebral glucose metabolic rate (Tmax/CMRglucose) than lean participants (2.12 ± 0.51 vs. 2.67 ± 0.51; p = 0.04). The cerebral tricarboxylic acid cycle flux (VTCA) was similar between the two groups (p = 0.64). There was a negative correlation between total nonesterified fatty acids and Tmax/CMRglucose (r = -0.477; p = 0.045). CONCLUSIONS: We conclude that CMRglucose is unlikely to differ between groups due to similar VTCA, and, therefore, the glucose transport Tmax is lower in individuals with obesity. These human findings suggest that obesity is associated with reduced cerebral glucose transport capacity even at a young age and in the absence of other cardiometabolic comorbidities, which may have implications for long-term brain function and health.
Asunto(s)
Encéfalo , Glucosa , Resistencia a la Insulina , Obesidad , Humanos , Adulto , Obesidad/metabolismo , Masculino , Femenino , Glucosa/metabolismo , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Adulto Joven , Glucemia/metabolismo , Espectroscopía de Resonancia Magnética , Ciclo del Ácido Cítrico , Transporte Biológico , Técnica de Clampeo de la Glucosa , Metabolismo Energético , Ácidos Grasos no Esterificados/sangre , Ácidos Grasos no Esterificados/metabolismo , Imagen por Resonancia MagnéticaRESUMEN
Due to the rise in overnutrition, the incidence of obesity-induced hepatocellular carcinoma (HCC) will continue to escalate; however, our understanding of the obesity to HCC developmental axis is limited. We constructed a single-cell atlas to interrogate the dynamic transcriptomic changes during hepatocarcinogenesis in mice. Here we identify fatty acid binding protein 5 (FABP5) as a driver of obesity-induced HCC. Analysis of transformed cells reveals that FABP5 inhibition and silencing predispose cancer cells to lipid peroxidation and ferroptosis-induced cell death. Pharmacological inhibition and genetic ablation of FABP5 ameliorates the HCC burden in male mice, corresponding to enhanced ferroptosis in the tumour. Moreover, FABP5 inhibition induces a pro-inflammatory tumour microenvironment characterized by tumour-associated macrophages with increased expression of the co-stimulatory molecules CD80 and CD86 and increased CD8+ T cell activation. Our work unravels the dual functional role of FABP5 in diet-induced HCC, inducing the transformation of hepatocytes and an immunosuppressive phenotype of tumour-associated macrophages and illustrates FABP5 inhibition as a potential therapeutic approach.
Asunto(s)
Carcinoma Hepatocelular , Proteínas de Unión a Ácidos Grasos , Ferroptosis , Neoplasias Hepáticas , Proteínas de Neoplasias , Obesidad , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/etiología , Animales , Proteínas de Unión a Ácidos Grasos/metabolismo , Proteínas de Unión a Ácidos Grasos/genética , Ratones , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/etiología , Obesidad/complicaciones , Obesidad/metabolismo , Masculino , Microambiente Tumoral/inmunología , Humanos , Ratones Endogámicos C57BL , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/inmunologíaRESUMEN
Volumetric muscle loss (VML) represents a clinical challenge due to the limited regenerative capacity of skeletal muscle. Most often, it results in scar tissue formation and loss of function, which cannot be prevented by current therapies. Decellularized extracellular matrix (DEM) has emerged as a native biomaterial for the enhancement of tissue repair. Here, we report the generation and characterization of hydrogels derived from DEM prepared from WT or thrombospondin (TSP)-2 null muscle tissue. TSP2-null hydrogels, when compared to WT, displayed altered architecture, protein composition, and biomechanical properties and allowed enhanced invasion of C2C12 myocytes and chord formation by endothelial cells. They also displayed enhanced cell invasion, innervation, and angiogenesis following subcutaneous implantation. To evaluate their regenerative capacity, WT or TSP2 null hydrogels were used to treat VML injury to tibialis anterior muscles and the latter induced greater recruitment of repair cells, innervation, and blood vessel formation and reduced inflammation. Taken together, these observations indicate that TSP2-null hydrogels enhance angiogenesis and promote muscle repair in a VML model.
Asunto(s)
Células Endoteliales , Hidrogeles , Hidrogeles/farmacología , Angiogénesis , Matriz Extracelular/metabolismo , Músculo Esquelético , NeurogénesisRESUMEN
Suspicious non-calcified mammographic findings have not been evaluated with modern mammographic technique, and the purpose of this work is to compare the likelihood of malignancy for those findings. To do this, 5018 consecutive mammographically guided biopsies performed during 2016-2019 at a large metropolitan, community-based hospital system were retrospectively reviewed. In total, 4396 were excluded for targeting calcifications, insufficient follow-up, or missing data. Thirty-seven of 126 masses (29.4%) were malignant, 44 of 194 asymmetries (22.7%) were malignant, and 77 of 302 architectural distortions (AD, 25.5%) were malignant. The combined likelihood of malignancy was 25.4%. Older age was associated with a higher likelihood of malignancy for each imaging finding type (all p ≤ 0.006), and a possible ultrasound correlation was associated with a higher likelihood of malignancy when all findings were considered together (p = 0.012). Two-view asymmetries were more frequently malignant than one-view asymmetries (p = 0.03). There were two false-negative biopsies (98.7% sensitivity and 100% specificity). In conclusion, the 25.4% likelihood of malignancy confirms the recommendation for biopsy of suspicious, ultrasound-occult, mammographic findings. Mammographically guided biopsies were highly sensitive and specific in this study. Older patient age and a possible ultrasound correlation should raise concern given the increased likelihood of malignancy in those scenarios.
RESUMEN
Several clinical studies observed a surprising beneficial effect of obesity on enhancing immunotherapy responsiveness in patients with melanoma, highlighting an as-yet insufficiently understood relationship between metabolism and immunogenicity. Here, we demonstrate that the thiazolidinedione (TZD) rosiglitazone, a drug commonly used to treat diabetes by sequestering fatty acids in metabolically inert subcutaneous adipose tissue, improved sensitivity to anti-programmed cell death protein 1 (PD-1) treatment in YUMMER1.7 tumor-bearing mice, an initially immunotherapy-sensitive murine melanoma model. We observed a transition from high to intermediate PD-1 expression in tumor-infiltrating CD8+ T cells. Moreover, TZD inhibited PD-1 expression in mouse and human T cells treated in vitro. In addition to its direct impact on immune cells, TZD also decreased circulating insulin concentrations, while insulin induced T cell exhaustion in culture. In TZD-treated mice, we observed higher fatty acid concentrations in the tumor microenvironment, with fatty acids protecting against exhaustion in culture. Together, these data are consistent with an indirect mechanism of TZD inhibiting T cell exhaustion. Finally, we analyzed imaging data from patients with melanoma before and after anti-PD-1 treatment, confirming the beneficial effect of increased subcutaneous fat on anti-PD-1 responsiveness in patients. We also found that the expression of peroxisome proliferator-activated receptor gamma (PPARγ), the canonical activator of lipid uptake and adipogenesis activated by TZD, correlated with overall survival time. Taken together, these data identify a new adjuvant to enhance immunotherapy efficacy in YUMMER1.7 melanoma mice, and discover a new metabolism-based prognostic marker in human melanoma.NEW & NOTEWORTHY Zhang et al. demonstrate that the diabetes drug rosiglitazone improves the efficacy of immunotherapy in mouse melanoma. This effect is both direct and indirect: TZD directly reduces PD-1 expression in CD8+ T cells (i.e., reduces exhaustion), and indirectly reduces exhaustion by lowering insulin levels and increasing local fat. Finally, they demonstrate that hallmarks of TZD action (such as PPARγ expression and subcutaneous fat content) correlate with improved immunotherapy efficacy in humans with melanoma.
Asunto(s)
Diabetes Mellitus , Melanoma , Tiazolidinedionas , Humanos , Animales , Ratones , Melanoma/tratamiento farmacológico , Rosiglitazona , Receptor de Muerte Celular Programada 1 , PPAR gamma , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Anticuerpos Monoclonales , Insulina , Ácidos Grasos , Microambiente TumoralRESUMEN
Cancer-related fatigue (CRF) is one of the most prevalent and detrimental complications of cancer. Emerging evidence suggests that obesity and insulin resistance are associated with CRF occurrence and severity in cancer patients and survivors. In this narrative review, we analyzed recent studies including both preclinical and clinical research on the relationship between obesity and/or insulin resistance and CRF. We also describe potential mechanisms for these relationships, though with the caveat that because the mechanisms underlying CRF are incompletely understood, the mechanisms mediating the association between obesity/insulin resistance and CRF are similarly incompletely delineated. The data suggest that, in addition to their effects to worsen CRF by directly promoting tumor growth and metastasis, obesity and insulin resistance may also contribute to CRF by inducing chronic inflammation, neuroendocrinological disturbance, and metabolic alterations. Furthermore, studies suggest that patients with obesity and insulin resistance experience more cancer-induced pain and are at more risk of emotional and behavioral disruptions correlated with CRF. However, other studies implied a potentially paradoxical impact of obesity and insulin resistance to reduce CRF symptoms. Despite the need for further investigation utilizing interventions to directly elucidate the mechanisms of cancer-related fatigue, current evidence demonstrates a correlation between obesity and/or insulin resistance and CRF, and suggests potential therapeutics for CRF by targeting obesity and/or obesity-related mediators.
Asunto(s)
Resistencia a la Insulina , Neoplasias , Humanos , Neoplasias/complicaciones , Obesidad/complicaciones , Fatiga/etiologíaRESUMEN
The kidneys facilitate energy conservation through reabsorption of nutrients including glucose. Almost all of the filtered blood glucose is reabsorbed by the kidneys. Loss of glucose in urine (glycosuria) is offset by an increase in endogenous glucose production to maintain normal energy supply in the body. How the body senses this glucose loss and consequently enhances glucose production is unclear. Using renal Glut2 knockout mice, we demonstrate that elevated glycosuria activates the hypothalamic-pituitary-adrenal axis, which in turn drives endogenous glucose production. This phenotype was attenuated by selective afferent renal denervation, indicating the involvement of the afferent nerves in promoting the compensatory increase in glucose production. In addition, through plasma proteomics analyses we observed that acute phase proteins - which are usually involved in body's defense mechanisms against a threat - were the top candidates which were either upregulated or downregulated in renal Glut2 KO mice. Overall, afferent renal nerves contribute to promoting endogenous glucose production in response to elevated glycosuria and loss of glucose in urine is sensed as a biological threat in mice. These findings may be useful in improving efficiency of drugs like SGLT2 inhibitors that are intended to treat hyperglycemia by enhancing glycosuria, but are met with a compensatory increase in endogenous glucose production.
RESUMEN
INTRODUCTION: Delirium is a syndrome characterised by a disturbance in attention, awareness and cognition as a result of another physical condition. It occurs in up to 50% of patients after cardiac surgery and is associated with increased mortality, prolonged intensive care and hospital stay and long-term cognitive dysfunction. Identifying effective preventive interventions is important. We will therefore conduct a systematic review to identify all randomised controlled studies that have tested a pharmacological or non-pharmacological intervention to prevent delirium. METHODS AND ANALYSIS: We will search electronic databases (CDSR (Reviews), CENTRAL (Trials), MEDLINE Ovid, Embase Ovid, PsycINFO Ovid) as well as trial registers (clinicaltrials.gov and ISCRTN) for randomised controlled trials of both pharmacological and non-pharmacological interventions designed to prevent delirium after cardiac surgery in adults. Screening of search results and data extraction from included articles will be performed by two independent reviewers using Rayyan. The primary outcome will be the incidence of delirium. Secondary outcomes include: duration of postoperative delirium, all-cause mortality, length of postoperative hospital and intensive care stay, postoperative neurological complications other than delirium, health-related quality of life and intervention-specific adverse events. Studies will be assessed for risk of bias using the Cochrane RoB2 tool. A narrative synthesis of all included studies will be presented and meta-analysis (if appropriate network meta-analysis) will be undertaken where there are sufficient studies (three or more) for pooling results. Results will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. ETHICS AND DISSEMINATION: No ethical approval is required. This review will be disseminated via peer-reviewed manuscript and conferences. PROSPERO REGISTRATION NUMBER: CRD42022369068.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Delirio , Adulto , Humanos , Delirio/etiología , Delirio/prevención & control , Calidad de Vida , Revisiones Sistemáticas como Asunto , Metaanálisis como Asunto , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/etiología , Literatura de Revisión como AsuntoRESUMEN
Recently, fasting-mimicking diet and caloric restriction have been shown to improve antitumor immunity. In this issue of Cancer Research, Zhong and colleagues provide insights into the molecular mechanism of fasting-mimicking diet-mediated metabolic reprogramming in colorectal cancer progression. The authors performed comprehensive mechanistic experiments in mouse models to show that fasting-mimicking diet prevents colorectal cancer progression by lowering intratumoral IgA+ B cells by accelerating fatty acid oxidation to inhibit B-cell IgA class switching. In addition, they found that fatty acid oxidation-dependent acetylation prevents IgA class switching and that IgA+ B cells interfere with the anticancer effects of fasting-mimicking diet in colorectal cancer. Overall, their study establishes that fasting-mimicking diet has the potential to activate anticancer immunity and to induce tumor regression in colorectal cancer. See related article by Zhong et al., p. 3529.
Asunto(s)
Neoplasias Colorrectales , Ayuno , Animales , Ratones , Ayuno/fisiología , Dieta , Restricción Calórica , Neoplasias Colorrectales/terapia , Inmunoglobulina A , Ácidos GrasosRESUMEN
L-type Amino Acid Transporter 1 (LAT1) facilitates the uptake of specific essential amino acids, and due to this quality, it has been correlated to worse patient outcomes in various cancer types. However, the relationship between LAT1 and various clinical factors, including menopausal status, in mediating LAT1's prognostic effects remains incompletely understood. This is particularly true in the unique subset of tumors that are both obesity-associated and responsive to immunotherapy, including breast cancer. To close this gap, we employed 6 sets of transcriptomic data using the Kaplan-Meier model in the Xena Functional Genomics Explorer, demonstrating that higher LAT1 expression diminishes breast cancer patients' survival probability. Additionally, we analyzed 3'-Deoxy-3'-18F-Fluorothymidine positron emission tomography-computed tomography (18F-FLT PET-CT) images found on The Cancer Imaging Archive (TCIA). After separating all patients based on menopausal status, we correlated the measured 18F-FLT uptake with various clinical parameters quantifying body composition, tumor proliferation, and immune cell infiltration. By analyzing a wealth of deidentified, open-access data, the current study investigates the impact of LAT1 expression on breast cancer prognosis, along with the menopausal status-dependent associations between tumor proliferation, immunometabolism, and systemic metabolism.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Menopausia , Transportador de Aminoácidos Neutros Grandes 1/genética , Tomografía de Emisión de Positrones/métodosRESUMEN
Cancer-related fatigue (CRF) is one of the most common complications in patients with multiple cancer types and severely affects patients' quality of life. However, there have only been single symptom-relieving adjuvant therapies but no effective pharmaceutical treatment for the CRF syndrome. Dichloroacetate (DCA), a small molecule inhibitor of pyruvate dehydrogenase kinase, has been tested as a potential therapy to slow tumor growth, based largely on its effects in vitro to halt cell division. We found that although DCA did not affect rates of tumor growth or the efficacy of standard cancer treatment (immunotherapy and chemotherapy) in two murine cancer models, DCA preserved physical function in mice with late-stage tumors by reducing circulating lactate concentrations. In vivo liquid chromatography-mass spectrometry/mass spectrometry studies suggest that DCA treatment may preserve membrane potential, postpone proteolysis, and relieve oxidative stress in muscles of tumor-bearing mice. In all, this study provides evidence for DCA as a novel pharmaceutical treatment to maintain physical function and motivation in murine models of CRF.NEW & NOTEWORTHY We identify a new metabolic target for cancer-related fatigue, dichloroacetate (DCA). They demonstrate that in mice, DCA preserves physical function and protects against the detrimental effects of cancer treatment by reducing cancer-induced increases in circulating lactate. As DCA is already FDA approved for another indication, these results could be rapidly translated to clinical trials for this condition for which no pharmaceutical therapies exist beyond symptom management.
Asunto(s)
Ácido Dicloroacético , Fatiga , Melanoma , Calidad de Vida , Animales , Ratones , Ácido Dicloroacético/farmacología , Ácido Dicloroacético/uso terapéutico , Fatiga/tratamiento farmacológico , Fatiga/etiología , Ácido Láctico/metabolismo , Melanoma/complicacionesRESUMEN
Female breast cancer is the most frequently diagnosed cancer. The long-term survival rates for this disease have increased; however, the unique demand for high-quality healthcare to improve breast-cancer survivorship are commonly unmet. The Mediterranean diet (MD) is associated with reduced breast-cancer risk and various health-related benefits in the general population, but its effect on breast-cancer survivors remains uncertain. The objective of this systematic review and meta-analysis was to assess current evidence from randomised controlled trials (RCTs) and observational studies (cohort, cross-sectional and case-control) regarding the effect of the MD on survival, quality of life (QoL) and health-related outcomes in female breast-cancer survivors. MEDLINE, EMBASE, Web of Science and the Cochrane library were searched for studies published before and including April 2022. Two reviewers independently screened the literature and completed the data extraction and risk-of-bias assessment. Eleven studies (fifteen reports) were included, including two RCTs, four cohort and five cross-sectional studies. The meta-analysis of the cohort studies showed strong evidence of an inverse association between high adherence to the MD and all-cause mortality (hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.66-0.93, I2: 0%, Grading of Recommendations Assessment, Development and Evaluation (GRADE) = low certainty of evidence) and non-breast-cancer mortality (HR 0.67, 95% CI 0.50-0.90, I2: 0%, GRADE = very low certainty of evidence). The associations between high adherence to the MD and QoL and health-related parameters were not consistent. These findings highlight the potential of adherence to the MD to reduce the risk of mortality. Future research with better study designs, as well as more consistent measurements of QoL and MD adherence, taking into account changes in MD adherence over time and population subgroups, is needed to provide more robust evidence on the survival, QoL and health-related outcomes in BC survivors.
Asunto(s)
Neoplasias de la Mama , Supervivientes de Cáncer , Dieta Mediterránea , Femenino , Humanos , Mama , Proyectos de Investigación , Estudios Observacionales como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged a deeper understanding of the tissue-specific metabolic response to sepsis. The current study sought to fill this gap. We analyzed skeletal muscle transcriptomics of critically ill patients, versus elective surgical controls, which revealed reduced expression of genes involved in mitochondrial metabolism and electron transport, with increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. We then performed untargeted metabolomics and 13C isotope tracing to analyze systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model. We found an increased number of correlations between the metabolomes of liver, kidney, and spleen, with loss of correlations between the heart and quadriceps and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for muscles during sepsis. A lowered GSH:GSSG and elevated AMP:ATP ratio in the liver underlie the significant upregulation of isotopically labeled glutamine's contribution to TCA cycle anaplerosis and glutamine-derived glutathione biosynthesis; meanwhile, the skeletal muscle and spleen were the only organs where glutamine's contribution to the TCA cycle was significantly suppressed. These results highlight tissue-specific mitochondrial reprogramming to support liver energetic demands and antioxidant synthesis, rather than global mitochondrial dysfunction, as a metabolic consequence of sepsis.